Hindawi Publishing CorporationScientificaVolume 2013 Article ID 580968 20 pageshttpdxdoiorg1011552013580968

Review ArticleType I Interferon at the Interface of Antiviral Immunity andImmune Regulation The Curious Case of HIV-1

Adriano Boasso

Immunology Section Chelsea and Westminster Hospital 369 Fulham Road London SW10 9NH UK

Correspondence should be addressed to Adriano Boasso aboassoimperialacuk

Received 12 November 2013 Accepted 10 December 2013

Academic Editors G Chen and M Clementi

Copyright copy 2013 Adriano Boasso This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Type I interferon (IFN-I) play a critical role in the innate immune response against viral infectionsThey actively participate in anti-viral immunity by inducing molecular mechanisms of viral restriction and by limiting the spread of the infection but they alsoorchestrate the initial phases of the adaptive immune response and influence the quality of T cell immunity During infectionwith the human immunodeficiency virus type 1 (HIV-1) the production of and response to IFN-I may be severely altered by thelymphotropic nature of the virus In this review I consider the different aspects of virus sensing IFN-I production signalling andeffects on target cells with a particular focus on the alterations observed following HIV-1 infection

1 IntroductionInterferons (IFN) are a heterogeneous class of soluble imm-une mediators which were originally defined by their abilityto interfere with the replication of diverse types of viruses invitro and in vivo Human type I IFN (IFN-I) include IFN-120572(14 genes resulting in more than 22 products) and IFN-120573both encoded by genes clustered on chromosome 9 probablygenerated as a result of gene duplication events as epitomizedby the presence of multiple pseudogenes [1] IFN-120576 IFN-120581IFN-120591 and IFN-120596 have also been described in mammals asmembers of the IFN-I family This review is focused on theliterature covering the regulation and the function of IFN-120572and IFN-120573

IFN-I are produced in large quantities in response to viralinfections and are generally regarded as a key bridgingmech-anismbetween innate and adaptive immune responses exert-ing both antiviral activity and immunostimulatory functionssuch as promoting antigen-presenting cell maturation andmolding T helper cell responses [2ndash8] However the notionthat IFN-I serve only as effector immune mechanisms mayneed to be revised based on accumulating evidence whichhighlights the potent immunoregulatory ability of these mol-ecules During chronic viral infections the beneficial antivi-ral and immunostimulatory effects of IFN-Imay be overruledby the prolonged stimulation of IFN-I-induced cytostatic andproapoptotic mechanisms

Infection by the human immunodeficiency virus type 1(HIV-1) may represent an extreme example of how chronicIFN-I production progressively undermines the developmentof efficient long-term antiviral immunity [9 10]

Different cells have the potential to produce IFN-I andthe mechanism by which viral insults are sensed varies depe-nding on the cell type as does the potency of the IFN-I-pro-ducing response In the case of HIV-1 most studies havefocussed on plasmacytoid dendritic cells (pDC) as the mainproducers of IFN-I following viral exposure [9 11 12] How-ever recent evidence indicates that the source and dynamicsof IFN-I production may change during the course of infe-ction and pDC may be replaced by myeloid dendritic cells(mDC) and monocytesmacrophages as the main source ofIFN-I during the transition from acute to chronic infection[13]

Based on themolecularmechanisms of viral sensing invo-lved in HIV-1 recognition by different cells (1) the evidenceavailable on IFN-I production by different cell types duringthe acute and chronic phases of infection (2) and the combi-nation of antiviral and immunomodulatory activity of IFN-I(3) it is possible to speculate that IFN-I may serve differentpurposes during different stages of chronic infections andthat the dysregulation of IFN-I production during HIV-1 infection may contribute to progressive immunodefici-ency

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2 Viral Sensing byPattern Recognition Receptors

Innate sensing of virus-related pathogen associated molecu-lar patterns (PAMP) relies primarily on recognition of viralnucleic acids by toll-like receptors (TLR) in the endosomesof specialised immune cells or by cytoplasmic sensors widelyexpressed by different cell types and not restricted to immunecells [14ndash19]

HIV-1 interacts with and infects cells expressing CD4which is engaged by the viral envelope glycoprotein gp120Thus IFN-I production duringHIV-1 infection ismainly sus-tained by immune cells which are either exposed to or infe-cted by HIV-1

21 Toll Like Receptors Toll-like receptors are a family ofpattern recognition receptors (PRR) preferentially expressedby cells which participate in the innate immune responsesagainst invading pathogens [14ndash16] At least four TLR havethe potential to sense viral nucleic acids in humans Signallingvia TLR3 TLR7 and TLR8 is triggered by viral RNA whereasTLR9 recognizes unmethylated CpG-rich DNA sequences[15 20] Although RNA-sensing TLR have the potential torecognizeHIV-1 only TLR7-expressing pDCappear to respo-nd promptly to viral exposure Conversely the available evi-dence either excludes or is inconclusive regarding the abilityof HIV-1 to directly activate cells expressing TLR8 or TLR3such as mDC and MΦ but also microglia and astrocyteswithin the central nervous system [12 21ndash23]

The ability of pDC to respond to HIV-1 stimulation appe-ars to bemainly dependent on TLR7 signalling [24] althougha role for TLR9 cannot be excluded [12]TheHIV-1 viral cycleincludes the formation of a DNARNA heterodimer and adouble stranded DNA proviral DNA which represent pote-ntial ligands for TLR9 via CpG-rich DNA regions Partialreverse transcription may occur already in the virion dueto the packaging of complexes formed by reverse transcrip-tase viral RNA genome and transfer RNA primer [25ndash27]However the reverse transcription process is completed inthe cytoplasmic environment [25 27] secluded from endo-somal TLR9 Whether fragment of DNA of viral originincluded in the virion engulfed by pDC and processed via theendosomal pathway can trigger TLR9-mediated responsesremains untested

Engagement of TLR79 results in the activation of acomplex network of transduction signalling pathways inpDC The first step required for TLR79 signal transductionis the recruitment of the adaptor molecule myeloid differen-tiation primary-response gene 88 (MyD88) which in turnassociates with other adaptor and signalling molecules toform a complex comprised of TNF-receptor-associated factor(TRAF)6 Brutonrsquos tyrosine kinase (BTK) IL-1R-associatedkinase (IRAK)4 and IRAK1 [20 28 29] The signalling com-plex catalyzes the activation of different intracellular path-ways

The pathwaymediated by the interferon regulatory factor(IRF)7 is directly associated with activation of IFN-120572 andIFN-120573 genes following nuclear translocation of IRF7 [30]Signalling through the IRF7 pathway is dependent on the

activation of phosphatidylinositol 3-kinase (PI3K)-120575 [31]IFN-120572120573 secreted during this early phase may act in anautocrine manner through the dimeric type I IFN receptor(IFNAR) and stimulate de novo production of IRF7 furtherstimulating IFN-I secretion in a potent positive feedbackloop of IFN-I production [28] The IRF7-mediated signall-ing pathway is therefore responsible for the differentiation ofpDC into efficient IFN-I producing cells (IPC) PI3K andIRF7 signalling is not required for the production of tumornecrosis factor (TNF)-120572 interleukin (IL)-6 and the che-mokines CXCL10 and CCL3 which rely on the canonicalnuclear factor (NF)-120581B pathway (Rel-A p50 dimer) whichin turn requires mitogen-activated protein kinase p38 (p38-MAPK) activity [32] The same pathway is responsible forpromoting the expression of the costimulatory moleculesCD80 and CD86 which are conditions necessary for thematuration of pDC into fully competent antigen presentingcells (APC) [32] TLR79 engagement also promotes upregu-lation of the immunoregulatory enzyme indoleamine (23)-dioxygenase (IDO) in both murine and human pDC [33ndash36] In murine models IDO regulation via TLR79 occursfollowing activation of the noncanonical NF-120581B pathway(Rel-B p52 complex) [37] and non-canonical NF-120581B is alsorequired to support IFN-120572 production [38]

IRF7 and NF-120581B are not simultaneously activated follow-ing TLR79 engagement and the pathway which dominatesthe signalling cascade is determined by the intracellularcompartment where TLR79 engagement occurs [39]

22 Cytoplasmic RNA Sensors TLR represent powerful mec-hanisms for viral recognition but their expression is limitedto immune cells and the restriction to endosomal comp-artment prevents them from detecting viruses which havereached the cytoplasmic environment Retinoic acid-indu-cible gene 1 (RIG-I)-like receptors (RLR) are a family of PRRbroadly expressed among different human cells and conferthe ability to sense virus-derived RNA within the cytopl-asm [15 17 18] RLR include RIG-I melanoma differentia-tion factor (MDA)5 and laboratory of genetics and phys-iology (LGP)2 protein all of which are potently upregulatedby IFN-I [40] Studies conducted in transgenic mice sug-gest that different RLR are critical in the recognition ofand IFN-I response against different viruses [18] How-ever it remains unclear how RLR distinguish viral RNAfrom cellular RNA and therefore trigger IFN-I produc-tion only in infected cells The specificity for exogenousRNA may be dependent on the recognition of second-ary structures which are common in viral RNA genomes[18] RLR signal transduction occurs through binding ofthe receptor to the mitochondrial adaptor IFN-120573 prom-oter stimulator (IPS)-1 and formation of a signalling com-plex leading to the activation of the kinases TNF rece-ptor-associated factor (TRAF)-associated NF-120581B actvator(TANK) binding kinase (TBK)1-IK120573 kinase (IKK)120576 [40] TheTBK1-IKK120576 is then responsible for both IFN-I production viaIRF3 and IRF7 and for NF-kB activation [40]

Berg and colleagues demonstrated that genomic HIVRNA can trigger inflammatory responses in human periph-eral blood mononuclear cells (PBMC) via RIG-I recognition

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leading to production of the interleukin (IL)-6 TNF-120572IFN-120572 and IFN-120573 [41]The cellular sources of the proinflam-matory cytokines were not investigated in this study Itis plausible that during HIV-1 infection in vivo all cellssusceptible of infection have the potential to respond toHIV-1 genomic RNA via RIG-I sensing However the natureof the responses may differ depending on the target cellsand inflammatory responses may be differentially mediatedby DC and monocytemacrophages compared to CD4 Tlymphocytes

23 Cytoplasmic DNA Sensors The presence of a RNA-DNA hybrid during reverse transcription of the HIV-1 RNAgenome into dsDNA suggests that cytoplasmic recognition ofthe proviral DNA may occur before its translocation to thenucleus and integration into the host genome

The cytosol of eukaryotic cells is rich in enzymes withDNase activity which prevent accumulation of DNA in thecytoplasm [42] However when the preventive measuresexerted by cytoplasmic DNases fail DNA of viral originmay accumulate in the cytoplasm Double stranded DNAis a potent immune stimulator when present in the cytosolof target cells [43 44] and recent evidence indicates thatsingle-stranded DNA with specific signatures such as AT-rich regions is also a strong activator of immune responses[45] Sensing of cytoplasmic DNA triggers a cascade of signaltransduction orchestrated by the adaptormolecule stimulatorof interferon genes (STING) [46ndash49] leading to the produc-tion of proinflammatory and antiviral cytokines includingIFN-I [48] STING engages TBK1 to cause IRF3 activationand the STING-TBK1-IRF3 signaling axis is critical for IFN-Iinduction by cytosolic DNA [50]

Recent evidence indicates that cytosolic HIV-1-deriveddsDNA or RNADNA heterodimersmay trigger innate imm-une responses Gao and colleagues have used both themono-cytic cell line THP1 and primary human monocyte-derivedmacrophages and dendritic cells to show that HIV infectioninduces the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) which binds to andactivates STING resulting in the production of IFN-I [51]The production of IFN-120573 was strictly dependent on reversetranscription indicating that HIV-1 DNA acts as the initialtrigger for IFN-I production [51] Furthermore Jakobsen andcolleagues have shown that ssDNA generated from HIV-1proviral genome is a potent activator of IFN-I in primaryhumanmonocyte-derivedmacrophages [52] Single strandedHIV-1 DNA engages the IFN-inducible protein 16 (IFI16) inthe cytoplasmofmacrophages leading to the activation of theSTING-TBK1-IRF3 pathway [52]

3 Cellular Sources of IFN-I duringHIV-1 Infection

31 Plasmacytoid Dendritic Cells Plasmacytoid DC are themost potent producers of IFN-I in response to viral infections[16 53 54] Expression of endosomal TLR7 and TLR9 allowspDC to respond to both RNA and DNA viruses whichare engulfed and trafficked into the endosomal pathway

Upon TLR79 engagement pDC can mature into antigen-presenting cells (APC) or IFN-I-producing cells (IPC) andthe prevalence of one pathway over the other largely dependson the intracellular locale in which the TLR ligand triggers itsreceptor [23 39]Thus the engagement of TLR79 within theearly endosomes causes strong activation of the IRF7 pathwayvia an IFN-120572120573-dependent positive feedback resulting in theproduction of high quantities of IFN-120572 and pDC differen-tiation into IFN-I-producing cells (IPC) [39] Conversely ifthe TLR ligand is trafficked to the lysosomes or late endo-somes signal transduction via the NF-120581B pathway is favoredresulting in the upregulation of costimulatory molecules andmaturation into APC [39] OrsquoBrien and colleagues reportedthat HIV-1 is preferentially trafficked to the early endosomesof pDC which in turn promotes a persistently activated IPCstatus combined with partial or incomplete maturation [23]

The binding of the HIV-1 envelope glycoprotein gp120 toCD4 but not to the coreceptors CCR5 or CXCR4 is requiredfor virion engulfment and subsequent activation of pDC viaTLR7 engagement [12 55] The interaction between gp120and CD4 is stabilized by accessory interactions involvingcellular adhesion molecules on both the cell membrane andviral envelope allowing the formation of a stable bindinginterface between HIV-1 and the target cells [56ndash58] Thusthe envelope of newly formed HIV-1 virions incorporatescellular proteins derived from the host cell of origin [5657 59] these cell-derived proteins contribute to virus-cellinteractions and may modulate the dynamics of infectionof target cells and uptake by endocytotic cells [57ndash60] Inaddition the HIV-1 envelope is not homogenous but ratherorganized in a functional substructure enriched in tightlypacked cholesterol similar to the lipid rafts described ineukaryotic cells including human leukocytes [9 60 61] Theorganization of a functional virion-associated lipid raft isrequired to confer HIV-1 the ability to induce potent IFN-Iproduction via pDC stimulation [9] Thus the efficiency ofHIV-1 uptake by pDC and the potency of IFN-I inductionare strongly reduced if envelope-associated cholesterol iswithdrawn by chemical treatment [9] However cholesteroldepleted HIV-1 partially retains the ability to promote pDCmaturation into APC [9] suggesting that the integrity of thevirion-associated lipid raftmay not only reduce the efficiencyof HIV-1 uptake but also modify the dynamics of HIV-1trafficking and subsequent TLR signalling in favour NF-120581B-mediated APCmaturation rather than IRF7-dependent IFN-120572 production

Activation of pDCmayoccurwithin hours fromexposureto HIV-1 in vivo Intravaginal infection of rhesus macaquescaused rapid accumulation of activated pDC at the mucosalsite of infection which resulted inmacrophage inflammatoryprotein (MIP)-3120572-mediated chemoattraction and infectionof CCR5-expressing CD4 T cells contributing to the spreadof the infection to secondary lymphoid tissues [62] LubongSabado and colleagues reported that pDC relocate to lym-phoid tissues already during primary HIV-1 infection a con-dition which persists throughout the course of disease [63]However reports on IFN-120572 secretion by pDC in lymphoidtissues during chronic HIV-1 infection showed contrastingresults For example although IFN-120572 and upregulation of

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IFN-stimulated genes (ISG) has been reported in tissues fromHIV+ patients [64 65] Nascimbeni and colleagues showedthat pDC in the spleen of HIV-infected patients have animmature phenotype and do not contribute to the increasedIFN-120572 production [66] The state of partial or incompletepDCmaturation is confirmed in the study by Benlahrech andcolleagues who have recently shown that expression of theimmunoglobulin-like transcript (ILT) 7 a regulatory receptorexpressed by immature circulating pDC but not partiallydifferentiated cells [36] is reduced in pDC fromHIV-infectedpatients when viral replication is not efficiently controlled bytherapy [67]

Recent evidence suggests that pDC may be the predo-minant source of IFN-I only during the initial phases ofacute infection whereas mDC and macrophages becomeimportant producers of IFN-120572 when the course of infectiontransitions to the early chronic phase [13] Both mDC andmonocytemacrophages express TLR8 which has the poten-tial to recognize viral RNA [68 69] However several studieshave shown that in vitromaturation ofmDCandmonocyte inpresence of HIV-1 is a bystander effect occurring in responseto cytokines produced by HIV-1-activated pDC such as IFN-120572 and TNF-120572 [12 21ndash23] In addition even in conditionsin which TLR8 engagement occurs mDC do not respondby secreting IFN-I but rather mature into interleukin (IL)-12-secreting APC [68 69] Thus IFN-I production by mDCand macrophages during the post-acute and chronic phasesof HIV-1 infection may depend on molecular pathwaysother than sensing of extracellular viral particles virus viaendosomal TLR

32 MonocytesMacrophages and Myeloid Dendritic CellsEndosomal TLR allow recognition of nucleic acids fromviruses engulfed by specialized cells but may not senseviral genomes which have gained access to the cytoplasmIntracellular RLR and DNA sensors are triggered by viralgenome in the cytoplasm and induce the production ofantiviral and immunostimulatory cytokines such as IFN-120572and TNF-120572 [18] RLR are expressed by most cell types andtheir triggering requires that the viral genome has reachedthe cytoplasm a condition which is also necessary to achieveproductive infection of the target cell Conversely TLR79-mediated pDC responses would not be triggered during aproductive infectious cycle due to the segregation of thereceptors in the endosomal compartmentThismay representa critical difference between IFN-I responses orchestrated byuninfected pDC during the early phases of viral exposure andIFN-I production by productively infected cells during laterstages of infection

This transition from a pDC-mediated to an apparen-tly pDC-independent IFN-I response has been recently des-cribed in the HIV-1 simian model of simian immunodefi-ciency infection (SIV) of Rhesus macaques by Kader andcolleagues [13] Monocyte derived macrophages have beenshown to respond to HIV-1 proviral DNA via intracellularDNA sensors [51 52] and genomic HIV-1 RNA activatesinnate immune responses in peripheralmononuclear cells viaRLR [41] The question can be raised as to whether the mainsource of IFN-I changes during HIV-1 infection in relation

to a shift in the distribution of productively infected cellsamong different cell types Dendritic cells may act as catalystsfor the infection of CD4 T cells via cell-cell transfer [70 71]but activated CCR5+ CD4 T cells are the main target forinfection and the main source of viral replication throughoutthe acute phase [72 73] However the number of CCR5+ Tcells decreases progressively during acute infection both inthe periphery and in lymphoid tissues likely due to a com-bination of viral cytotoxicity activation-induced apoptosisand immune-dependent killing mediated by newly activatedHIV-1-specific cytotoxic CD8 T lymphocytes (CTL) [72ndash74]Thus as the pool of CCR5+ CD4 T cells decreases CD4-expressing mDC and monocytemacrophages may becomeincreasinglymore important as targets for infection and ther-efore more susceptible to activation via cytoplasmic RLR

The critical questions that remain unanswered is whetherthe prolonged IFN-I response observed during pathogenicHIV-1SIV infection plays a determinant role in viral immu-nopathogenesis and whether pDC-mediated acute responsesor chronic IFN-I responses mediated by non-pDC subsetsare potentially valuable targets for immunotherapeutic orcurative interventions

33 Other Cellular Sources of IFN-I The broad expression ofRLR and cytosolicDNA sensors in numerous cell types and indifferent tissues [18] suggests that any cell susceptible to HIV-1 infection and therefore to cytoplasmic exposure of viralRNA has the potential to secrete IFN-120572 during HIV-1 infec-tion Nonetheless evidence about IFN-120572 production by cellsother than DC and monocytes is scattered and largely incon-clusive about its relevance for systemic immune activationand immunopathogenesis However IFN-120572-producing cellsubsets which are confided to specific anatomic locationsmaycontribute to inflammatory processes within non lymphoidtissues and organs partially accounting for the develop-ment of HIV-1-associated non-communicable comorbidities(NCCM)An increasing body of evidence suggests a causativelink between chronic inflammation and some manifestationsof NCCM One example is that of neurological complica-tions associatedwith neuroinflammationwhich are observedeven in patients in whom viral replication in controlled bycombination antiretroviral therapy (cART) [75ndash77] Thusmicroglial activation and an IFN-driven gene regulation sig-nature are characteristic ofHIV-associated neurological sym-ptoms such as cognitive impairment and depressive disorder[75 76 78 79] It is noteworthy that neurologic diseaseassociated with infection with another human lymphotropicretrovirus the human T-lymphotropic virus type 1 (HTLV-1) is also associated with an IFN-dominated inflamma-tory profile Thus Tattermusch and colleagues describedan IFN-inducible signature in HTLV-1-associated myelopa-thytropical spastic paraparesis (HAMTSP) [80 81] It is stillunclear whether peripheral sources of IFN-I such as DC ormacrophages are the sole responsible for the neuropathologiceffects or whether astrocytes and microglial cells are directlyinvolved in the production of IFN-I during the inflammatoryresponse Whether IFN-I production by these cells plays arole also in the immunopathogenesis of HIV-1 infection is yetto be determined

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4 Effect of IFN-I on Target Cells

Type I IFN are the most potent natural mediators of antiviralactivity in humans The combination of proapoptotic andcytostatic activity as well as the direct induction of intracel-lular viral restriction factors contribute to generate a cellularenvironment which is unsuitable for viral replication [1 3 8283] The replication of HIV-1 is efficiently inhibited by IFN-I in vitro but the potential of IFN-I as antiretroviral agentsduring chronic HIV-1 infection in vivo is dubious [84ndash89]

IFN-I also contribute to the maturation of APC and exerta modulatory effect on different T cell subsets thereforeposing the foundations for promoting antigen-specific adap-tive immune responses and shaping them according to theinvading pathogen [1 6 7 53 82 90]

41 IFN-120572 Receptor Complex and Signalling The cellulareffects of IFN-I aremediated by the engagement of a commonreceptor complex the IFN-120572 receptor complex (IFNAR)which is expressed at different levels on the surface of virtuallyall human cells The IFNAR complex is a heterodimer of thetwo subunits IFNAR1 and IFNAR2 Human IFNAR1 com-prises an extracellular domain a transmembrane region andan intracellular domain of 100 amino acid residues Threedifferent forms of IFNAR2 have been described the fulllength receptor chain which includes a 250 residues cytoplas-mic portion an alternative form with a shorted intracellularportion (67 residues) [91 92] and a soluble form lackingthe transmembrane and cytoplasmic portions [91] HumanIFNAR2 binds all human IFN-I with higher affinity thanIFNAR1 but the affinity of the IFNAR heterodimer for mosthuman IFN-I is 10 fold higher than IFNAR2 alone [91 93 94]

The cytoplasmic domains of IFNAR1 and IFNAR2 areassociated with the tyrosine kinase (TYK)-2 and janus kin-ase (JAK)-1 respectively [91] Upon IFN-I binding to theIFNAR complex the tyrosine kinases are activated and orc-hestrate the signal transduction machinery [95] TYK-2and JAK-1 phosphorylate tyrosine residues on the IFNARand phosphorylated tyrosines act as docking sites for thesrc-homology-2 (SH2) domains of signal transducer andactivator of transcription (STAT) proteins which are thentargeted for phosphorylation [96 97] STAT1 STAT2 STAT3and STAT5 are expressed and activated by IFN-I in mostcell types whereas IFN-I-induced activation of STAT4 andSTAT6 is limited to lymphocytes [96 97]

STAT2 is recruited to the IFNAR1 cytoplasmic domainand is phosphorylated by TYK-2 serving as a lure for STAT1[98] which is also phosphorylated at tyrosine 701The STAT1-STAT2 heterodimer associates with the DNA binding proteininterferon regulatory factor 9 (IRF9) to form a signallingcomplex called IFN-stimulated gene factor-3 (ISGF3) TheISGF3 complex translocates to the nucleus where it promotesthe transcription of IFN-I-stimulated genes (ISG) by inter-acting with the IFN-stimulated response elements (ISRE)usually situated within 200 base pairs of the transcriptionstart site An additional phosphorilation of STAT1 at serine727 mediated by protein kinase C-120575 (PKC-120575) is essential forefficient transcriptional activity [1 98] In addition STAT1homodimers can bind to IFN-120574-activated site (GAS) in the

promoter region of IFN-I-stimulated genes [99 100] Thuswhile IFN-I can activate genes containing either ISRE or GASpromoter elements IFN-120574 is unable to induce the formationof ISGF3 and activate genes via ISRE [101] Signalling viaSTAT1-STAT2 is responsible for some of the most commonlyobserved effects of IFN-I during chronic HIV-1 infectionincluding the activation of proapoptotic and cytostatic genesviral restriction factors and immunomodulatory effects [102ndash104]

Type I IFN also triggers phosphorylation of STAT3[105] promoting its dimerization and migration to the nucl-eus STAT3 homodimers activate the transcription of genescontaining the enhancer sequence STAT3-binding element(SBE) Despite sharing high sequence similarity with STAT1STAT3 activation induces a gene expression profile distinctfrom that dependent on STAT1-STAT2 [106] including genesof the B cell lymphoma (BCL) family and the oncogeneMYC which promote proliferation and antagonize apoptosis[107 108] Furthermore STAT3 is responsible for the sup-pression of inflammatory responses via IL-10 which directlycounteracts STAT1 activity [109]

IFN-120573 also activates the signal transduction pathwaymediated by JAK1 and phosphoinositide 3-kinase (PI3K)leading to the expression of genes regulated by cyclic adeno-sine monophosphate (cAMP) via the nuclear translocation ofcAMP-responsive-element (CRE) binding protein (CREB)Similar to the STAT3-mediated pathway PI3K signalling canalso result in IL-10 production by DC [110] However thetwo pahways appear to be independent from each other Themammalian target of rapamycin (mTOR) is activated down-stream of the PI3K signalling cascade [111] Activation ofmTOR is independent of STAT signalling and does notmodify the gene expression profile but modulates mRNAtranslation by regulating the activation of p70 S6 kinase andthe phosphorylation of the ribosomal protein S6 [112 113]

The signalling pathway mediated by p38 mitogen-activ-ated protein kinases (p38-MAPK) and extracellular signal-regulated kinase (ERK) 1 or ERK2 is also activated by IFN-IThus genes which contain ISRE and GAS elements in theirpromoter region can be upregulated via a STAT-independentpathwaymediated by p38-MAPK [114ndash116] and the cytostaticand antiviral effects of IFN-I are dependent on intact p38-MAPK signalling machinery [117ndash120]

It is reasonable to expect that different IFN-I signaltransduction pathways are activated during HIV-1 infectionHowever the STAT1-STAT2 pathway is arguably the bestdescribed in the setting of IFN-I production during HIV-1 infection The activation of STAT proteins by HIV-1 wasdescribed in different experimental conditions involvingHIV-1-induced IFN-I production productive HIV-1 infec-tion of target cells or simple exposure to viral proteins Thusin vitro exposure of cell lines or primary leukocytes towhole HIV-1 virions was repeatedly shown to activate STAT-dependent pathways inCD4T cells and cells of themonocyticlineage [55 121 122] Interestingly Renga and colleaguesreported that exposure of monocytic cell lines to the HIV-1matrix protein p17 was sufficient to activate the JAK1STAT1axis and cause upregulation of STAT1 sensitive genes [123]suggesting that STAT1 activation during HIV-1 infectionmay

6 Scientifica

also occur independent of IFN-I production Simian immun-odeficiency virus (SIV) infection of nonhuman primates invivo resulted in upregulation of gene expression for STAT1STAT2 and IRF9 during the acute phase of infection whichwas protracted through the early chronic phase only indisease susceptible primate species not in disease resistantAfrican species [124 125] Although signalling via the ISGF3complex is regulated by post-transcriptional modification ofSTAT proteins not by modulation of STAT and IRF9 geneexpression the observed increases in the expression of thesemolecules in SIV-infectedmacaques [124 125] is indicative ofenhanced activity of the IFN-IISGF3 axis

The central role played by PI3K in multiple signal trans-duction pathways renders it difficult to distinguish its partici-pation in mediating the effects of IFN-I from other biochem-ical cellular and molecular events occurring during HIV-1infection The contribution of PI3K in neuroinflammationassociatedwithHIV-1 infection has been described [126ndash128]but the role of Pi3KmTOR in HIV-1 immunopathogenesisremains unclear

Activation of the p38-MAPK pathway during HIV-1 infe-ction has been described by several groups [129ndash139] How-ever studies on the p38-MAPKERK pathway have generallyfocused on the direct effect of HIV-1 gp120 singalling viaengagement of CD4 or the coreceptors CCR5 and CXCR4[129 136ndash139] rather than IFN-I production In particularactivation of p38-MAPKERK has been studied in referenceto its role in modulating cell activation and HIV-1 replication[129ndash135]

42 Expression Pattern of IFNAR Type I IFN are generallyconsidered to exert their biologic effect on virtually all humancells This broad and noncell specific activity reflects theprominent innate antiviral function of IFN-I which needs toreach any potential target of viral infection

However cell-specific differences in the responsivenessto IFN-I signalling have been observed in humans partic-ularly among immune effector cells Thus IFN-I inducingTLR9 agonists as well as HIV-1 efficiently upregulated theexpression of the IFN-I regulated gene PDL1 on primaryhuman monocytes and a subset of T lymphocytes identifiedby selective expression of the chemokine receptor CCR5 [21]Analysis of IFNAR2 expression in T lymphocytes revealedthat this subunit of IFNAR was almost exclusively restrictedto CCR5+ T cell subsets independent of whether CD4 orCD8 T cells were considered [21] A similar restriction ofIFN-I signalling to CCR5+ T cells was observed when HIV-1-induced upregulation of the T cell activationmarkers CD38and CD69 was analyzed in vitro [9 140]

In both humans and non-human primates CCR5 expres-sion is generally higher in memory and effector T cell subsets[141ndash144] and natural disease-resistant SIV host speciessuch as sooty mangabeys show reduced levels of CCR5+CD4 T cells compared to disease susceptible hosts such ashumans and Rhesus macaques [142 143] The role playedby CCR5 as coreceptor for HIV-1 and SIV Env proteinsproviding the critical mechanism for envelope-membranefusion and injection of the viral RNA into the cytoplasmprovided the basis for investigating how differences in CCR5

expression between different species translate into differenttransmission and disease progression phenotype [142 145]However little attention has been given to the possibility thatdifferent profiles of CCR5 expression among primate speciesmay account for different sensitivity to IFN-I production andtherefore different patterns of regulation of IFN-I-stimulatedgenes during chronic HIV-1 or SIV infection ultimatelyaccounting for differences in disease susceptibility

43 Cytostatic and Proapoptotic Effects Type I IFN are widelyrecognized as the most potent natural mediators of antiviralactivity in humans [1 3] Because the life cycle of viruses isdirectly influenced by the intracellular environment efficientantiviral mechanisms have developed to interfere with basiccellular functions or in an even more resolute mannereliminate infected cells which represent the factories ofviral replication These goals are achieved by IFN-I via theupregulation of genes exerting cytostatic and proapoptoticactivities The broadly effective antiviral mechanisms includethe induction of molecular mechanisms interfering with pro-tein synthesis and cellular activity as well as the stimulationof ligandreceptor-dependent apoptotic pathways and stressresponses While exerting potent antiretroviral activity thesemechanisms clearly interferewith basic cellular functions andcarry a potentially destructive risk for the host hence theneed for tight regulation of both the kinetic of activation andthe restriction to specific anatomical locations

During HIV-1 infection the chronic induction of IFN-Iresponses may contribute to progressive immunodeficiency[10 146]

431 Ligand-Receptor Mediated Apoptosis Type I IFN posi-tively regulates the expression of tumor necrosis factor (TNF)family members capable of inducing apoptosis in cells whichexpress specific receptors Thus expression of FAS ligand(FasL) TNF-related apoptosis inducing ligand (TRAIL) andprogrammed death ligand (PDL) 1 are all directly regulatedby IFN-I signalling [21 146ndash148]

The contribution of the FasFasL system to CD4 T cellapoptosis during HIV-1 infection is well documented [149ndash151] and similar findings were reported for IFN-I-inducedTRAIL and its death receptor (DR)5 [55 65 121 152 153]TRAIL expression following HIV-1 exposure or infection hasbeen described in T cells monocytes and pDC [24 55 153154] and TRAIL expressing pDChave been shown to directlyinduce apoptosis of CD4 T cells in HIV-1 infected patientswith high viraemia [153] TRAIL mediated apoptosis in thesetting of HIV-1 stimulation in vitro was originally reportedto affect CD4 T cells but not CD8 T cells [55 65 152]Interestingly TRAIL mediated CD4 T cell apoptosis did notrequire productive infection and TRAIL expressing pDCwere reported to be unable to lyse HIV-1 infected CD4 Tcells [155] possibly favouring the depletion of uninfectedCD4 T helper cells in the face of CD4 T cell viral reservoirspreservation However Zhu et al later described TRAILdependent apoptosis in HIV-1 infected macrophages as aresult of the downregulation of a decoy receptor [156]Thus TRIAL induced apoptosis may contribute to regulating

Scientifica 7

the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

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2 Scientifica

2 Viral Sensing byPattern Recognition Receptors

Innate sensing of virus-related pathogen associated molecu-lar patterns (PAMP) relies primarily on recognition of viralnucleic acids by toll-like receptors (TLR) in the endosomesof specialised immune cells or by cytoplasmic sensors widelyexpressed by different cell types and not restricted to immunecells [14ndash19]

HIV-1 interacts with and infects cells expressing CD4which is engaged by the viral envelope glycoprotein gp120Thus IFN-I production duringHIV-1 infection ismainly sus-tained by immune cells which are either exposed to or infe-cted by HIV-1

21 Toll Like Receptors Toll-like receptors are a family ofpattern recognition receptors (PRR) preferentially expressedby cells which participate in the innate immune responsesagainst invading pathogens [14ndash16] At least four TLR havethe potential to sense viral nucleic acids in humans Signallingvia TLR3 TLR7 and TLR8 is triggered by viral RNA whereasTLR9 recognizes unmethylated CpG-rich DNA sequences[15 20] Although RNA-sensing TLR have the potential torecognizeHIV-1 only TLR7-expressing pDCappear to respo-nd promptly to viral exposure Conversely the available evi-dence either excludes or is inconclusive regarding the abilityof HIV-1 to directly activate cells expressing TLR8 or TLR3such as mDC and MΦ but also microglia and astrocyteswithin the central nervous system [12 21ndash23]

The ability of pDC to respond to HIV-1 stimulation appe-ars to bemainly dependent on TLR7 signalling [24] althougha role for TLR9 cannot be excluded [12]TheHIV-1 viral cycleincludes the formation of a DNARNA heterodimer and adouble stranded DNA proviral DNA which represent pote-ntial ligands for TLR9 via CpG-rich DNA regions Partialreverse transcription may occur already in the virion dueto the packaging of complexes formed by reverse transcrip-tase viral RNA genome and transfer RNA primer [25ndash27]However the reverse transcription process is completed inthe cytoplasmic environment [25 27] secluded from endo-somal TLR9 Whether fragment of DNA of viral originincluded in the virion engulfed by pDC and processed via theendosomal pathway can trigger TLR9-mediated responsesremains untested

Engagement of TLR79 results in the activation of acomplex network of transduction signalling pathways inpDC The first step required for TLR79 signal transductionis the recruitment of the adaptor molecule myeloid differen-tiation primary-response gene 88 (MyD88) which in turnassociates with other adaptor and signalling molecules toform a complex comprised of TNF-receptor-associated factor(TRAF)6 Brutonrsquos tyrosine kinase (BTK) IL-1R-associatedkinase (IRAK)4 and IRAK1 [20 28 29] The signalling com-plex catalyzes the activation of different intracellular path-ways

The pathwaymediated by the interferon regulatory factor(IRF)7 is directly associated with activation of IFN-120572 andIFN-120573 genes following nuclear translocation of IRF7 [30]Signalling through the IRF7 pathway is dependent on the

activation of phosphatidylinositol 3-kinase (PI3K)-120575 [31]IFN-120572120573 secreted during this early phase may act in anautocrine manner through the dimeric type I IFN receptor(IFNAR) and stimulate de novo production of IRF7 furtherstimulating IFN-I secretion in a potent positive feedbackloop of IFN-I production [28] The IRF7-mediated signall-ing pathway is therefore responsible for the differentiation ofpDC into efficient IFN-I producing cells (IPC) PI3K andIRF7 signalling is not required for the production of tumornecrosis factor (TNF)-120572 interleukin (IL)-6 and the che-mokines CXCL10 and CCL3 which rely on the canonicalnuclear factor (NF)-120581B pathway (Rel-A p50 dimer) whichin turn requires mitogen-activated protein kinase p38 (p38-MAPK) activity [32] The same pathway is responsible forpromoting the expression of the costimulatory moleculesCD80 and CD86 which are conditions necessary for thematuration of pDC into fully competent antigen presentingcells (APC) [32] TLR79 engagement also promotes upregu-lation of the immunoregulatory enzyme indoleamine (23)-dioxygenase (IDO) in both murine and human pDC [33ndash36] In murine models IDO regulation via TLR79 occursfollowing activation of the noncanonical NF-120581B pathway(Rel-B p52 complex) [37] and non-canonical NF-120581B is alsorequired to support IFN-120572 production [38]

IRF7 and NF-120581B are not simultaneously activated follow-ing TLR79 engagement and the pathway which dominatesthe signalling cascade is determined by the intracellularcompartment where TLR79 engagement occurs [39]

22 Cytoplasmic RNA Sensors TLR represent powerful mec-hanisms for viral recognition but their expression is limitedto immune cells and the restriction to endosomal comp-artment prevents them from detecting viruses which havereached the cytoplasmic environment Retinoic acid-indu-cible gene 1 (RIG-I)-like receptors (RLR) are a family of PRRbroadly expressed among different human cells and conferthe ability to sense virus-derived RNA within the cytopl-asm [15 17 18] RLR include RIG-I melanoma differentia-tion factor (MDA)5 and laboratory of genetics and phys-iology (LGP)2 protein all of which are potently upregulatedby IFN-I [40] Studies conducted in transgenic mice sug-gest that different RLR are critical in the recognition ofand IFN-I response against different viruses [18] How-ever it remains unclear how RLR distinguish viral RNAfrom cellular RNA and therefore trigger IFN-I produc-tion only in infected cells The specificity for exogenousRNA may be dependent on the recognition of second-ary structures which are common in viral RNA genomes[18] RLR signal transduction occurs through binding ofthe receptor to the mitochondrial adaptor IFN-120573 prom-oter stimulator (IPS)-1 and formation of a signalling com-plex leading to the activation of the kinases TNF rece-ptor-associated factor (TRAF)-associated NF-120581B actvator(TANK) binding kinase (TBK)1-IK120573 kinase (IKK)120576 [40] TheTBK1-IKK120576 is then responsible for both IFN-I production viaIRF3 and IRF7 and for NF-kB activation [40]

Berg and colleagues demonstrated that genomic HIVRNA can trigger inflammatory responses in human periph-eral blood mononuclear cells (PBMC) via RIG-I recognition

Scientifica 3

leading to production of the interleukin (IL)-6 TNF-120572IFN-120572 and IFN-120573 [41]The cellular sources of the proinflam-matory cytokines were not investigated in this study Itis plausible that during HIV-1 infection in vivo all cellssusceptible of infection have the potential to respond toHIV-1 genomic RNA via RIG-I sensing However the natureof the responses may differ depending on the target cellsand inflammatory responses may be differentially mediatedby DC and monocytemacrophages compared to CD4 Tlymphocytes

23 Cytoplasmic DNA Sensors The presence of a RNA-DNA hybrid during reverse transcription of the HIV-1 RNAgenome into dsDNA suggests that cytoplasmic recognition ofthe proviral DNA may occur before its translocation to thenucleus and integration into the host genome

The cytosol of eukaryotic cells is rich in enzymes withDNase activity which prevent accumulation of DNA in thecytoplasm [42] However when the preventive measuresexerted by cytoplasmic DNases fail DNA of viral originmay accumulate in the cytoplasm Double stranded DNAis a potent immune stimulator when present in the cytosolof target cells [43 44] and recent evidence indicates thatsingle-stranded DNA with specific signatures such as AT-rich regions is also a strong activator of immune responses[45] Sensing of cytoplasmic DNA triggers a cascade of signaltransduction orchestrated by the adaptormolecule stimulatorof interferon genes (STING) [46ndash49] leading to the produc-tion of proinflammatory and antiviral cytokines includingIFN-I [48] STING engages TBK1 to cause IRF3 activationand the STING-TBK1-IRF3 signaling axis is critical for IFN-Iinduction by cytosolic DNA [50]

Recent evidence indicates that cytosolic HIV-1-deriveddsDNA or RNADNA heterodimersmay trigger innate imm-une responses Gao and colleagues have used both themono-cytic cell line THP1 and primary human monocyte-derivedmacrophages and dendritic cells to show that HIV infectioninduces the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) which binds to andactivates STING resulting in the production of IFN-I [51]The production of IFN-120573 was strictly dependent on reversetranscription indicating that HIV-1 DNA acts as the initialtrigger for IFN-I production [51] Furthermore Jakobsen andcolleagues have shown that ssDNA generated from HIV-1proviral genome is a potent activator of IFN-I in primaryhumanmonocyte-derivedmacrophages [52] Single strandedHIV-1 DNA engages the IFN-inducible protein 16 (IFI16) inthe cytoplasmofmacrophages leading to the activation of theSTING-TBK1-IRF3 pathway [52]

3 Cellular Sources of IFN-I duringHIV-1 Infection

31 Plasmacytoid Dendritic Cells Plasmacytoid DC are themost potent producers of IFN-I in response to viral infections[16 53 54] Expression of endosomal TLR7 and TLR9 allowspDC to respond to both RNA and DNA viruses whichare engulfed and trafficked into the endosomal pathway

Upon TLR79 engagement pDC can mature into antigen-presenting cells (APC) or IFN-I-producing cells (IPC) andthe prevalence of one pathway over the other largely dependson the intracellular locale in which the TLR ligand triggers itsreceptor [23 39]Thus the engagement of TLR79 within theearly endosomes causes strong activation of the IRF7 pathwayvia an IFN-120572120573-dependent positive feedback resulting in theproduction of high quantities of IFN-120572 and pDC differen-tiation into IFN-I-producing cells (IPC) [39] Conversely ifthe TLR ligand is trafficked to the lysosomes or late endo-somes signal transduction via the NF-120581B pathway is favoredresulting in the upregulation of costimulatory molecules andmaturation into APC [39] OrsquoBrien and colleagues reportedthat HIV-1 is preferentially trafficked to the early endosomesof pDC which in turn promotes a persistently activated IPCstatus combined with partial or incomplete maturation [23]

The binding of the HIV-1 envelope glycoprotein gp120 toCD4 but not to the coreceptors CCR5 or CXCR4 is requiredfor virion engulfment and subsequent activation of pDC viaTLR7 engagement [12 55] The interaction between gp120and CD4 is stabilized by accessory interactions involvingcellular adhesion molecules on both the cell membrane andviral envelope allowing the formation of a stable bindinginterface between HIV-1 and the target cells [56ndash58] Thusthe envelope of newly formed HIV-1 virions incorporatescellular proteins derived from the host cell of origin [5657 59] these cell-derived proteins contribute to virus-cellinteractions and may modulate the dynamics of infectionof target cells and uptake by endocytotic cells [57ndash60] Inaddition the HIV-1 envelope is not homogenous but ratherorganized in a functional substructure enriched in tightlypacked cholesterol similar to the lipid rafts described ineukaryotic cells including human leukocytes [9 60 61] Theorganization of a functional virion-associated lipid raft isrequired to confer HIV-1 the ability to induce potent IFN-Iproduction via pDC stimulation [9] Thus the efficiency ofHIV-1 uptake by pDC and the potency of IFN-I inductionare strongly reduced if envelope-associated cholesterol iswithdrawn by chemical treatment [9] However cholesteroldepleted HIV-1 partially retains the ability to promote pDCmaturation into APC [9] suggesting that the integrity of thevirion-associated lipid raftmay not only reduce the efficiencyof HIV-1 uptake but also modify the dynamics of HIV-1trafficking and subsequent TLR signalling in favour NF-120581B-mediated APCmaturation rather than IRF7-dependent IFN-120572 production

Activation of pDCmayoccurwithin hours fromexposureto HIV-1 in vivo Intravaginal infection of rhesus macaquescaused rapid accumulation of activated pDC at the mucosalsite of infection which resulted inmacrophage inflammatoryprotein (MIP)-3120572-mediated chemoattraction and infectionof CCR5-expressing CD4 T cells contributing to the spreadof the infection to secondary lymphoid tissues [62] LubongSabado and colleagues reported that pDC relocate to lym-phoid tissues already during primary HIV-1 infection a con-dition which persists throughout the course of disease [63]However reports on IFN-120572 secretion by pDC in lymphoidtissues during chronic HIV-1 infection showed contrastingresults For example although IFN-120572 and upregulation of

4 Scientifica

IFN-stimulated genes (ISG) has been reported in tissues fromHIV+ patients [64 65] Nascimbeni and colleagues showedthat pDC in the spleen of HIV-infected patients have animmature phenotype and do not contribute to the increasedIFN-120572 production [66] The state of partial or incompletepDCmaturation is confirmed in the study by Benlahrech andcolleagues who have recently shown that expression of theimmunoglobulin-like transcript (ILT) 7 a regulatory receptorexpressed by immature circulating pDC but not partiallydifferentiated cells [36] is reduced in pDC fromHIV-infectedpatients when viral replication is not efficiently controlled bytherapy [67]

Recent evidence suggests that pDC may be the predo-minant source of IFN-I only during the initial phases ofacute infection whereas mDC and macrophages becomeimportant producers of IFN-120572 when the course of infectiontransitions to the early chronic phase [13] Both mDC andmonocytemacrophages express TLR8 which has the poten-tial to recognize viral RNA [68 69] However several studieshave shown that in vitromaturation ofmDCandmonocyte inpresence of HIV-1 is a bystander effect occurring in responseto cytokines produced by HIV-1-activated pDC such as IFN-120572 and TNF-120572 [12 21ndash23] In addition even in conditionsin which TLR8 engagement occurs mDC do not respondby secreting IFN-I but rather mature into interleukin (IL)-12-secreting APC [68 69] Thus IFN-I production by mDCand macrophages during the post-acute and chronic phasesof HIV-1 infection may depend on molecular pathwaysother than sensing of extracellular viral particles virus viaendosomal TLR

32 MonocytesMacrophages and Myeloid Dendritic CellsEndosomal TLR allow recognition of nucleic acids fromviruses engulfed by specialized cells but may not senseviral genomes which have gained access to the cytoplasmIntracellular RLR and DNA sensors are triggered by viralgenome in the cytoplasm and induce the production ofantiviral and immunostimulatory cytokines such as IFN-120572and TNF-120572 [18] RLR are expressed by most cell types andtheir triggering requires that the viral genome has reachedthe cytoplasm a condition which is also necessary to achieveproductive infection of the target cell Conversely TLR79-mediated pDC responses would not be triggered during aproductive infectious cycle due to the segregation of thereceptors in the endosomal compartmentThismay representa critical difference between IFN-I responses orchestrated byuninfected pDC during the early phases of viral exposure andIFN-I production by productively infected cells during laterstages of infection

This transition from a pDC-mediated to an apparen-tly pDC-independent IFN-I response has been recently des-cribed in the HIV-1 simian model of simian immunodefi-ciency infection (SIV) of Rhesus macaques by Kader andcolleagues [13] Monocyte derived macrophages have beenshown to respond to HIV-1 proviral DNA via intracellularDNA sensors [51 52] and genomic HIV-1 RNA activatesinnate immune responses in peripheralmononuclear cells viaRLR [41] The question can be raised as to whether the mainsource of IFN-I changes during HIV-1 infection in relation

to a shift in the distribution of productively infected cellsamong different cell types Dendritic cells may act as catalystsfor the infection of CD4 T cells via cell-cell transfer [70 71]but activated CCR5+ CD4 T cells are the main target forinfection and the main source of viral replication throughoutthe acute phase [72 73] However the number of CCR5+ Tcells decreases progressively during acute infection both inthe periphery and in lymphoid tissues likely due to a com-bination of viral cytotoxicity activation-induced apoptosisand immune-dependent killing mediated by newly activatedHIV-1-specific cytotoxic CD8 T lymphocytes (CTL) [72ndash74]Thus as the pool of CCR5+ CD4 T cells decreases CD4-expressing mDC and monocytemacrophages may becomeincreasinglymore important as targets for infection and ther-efore more susceptible to activation via cytoplasmic RLR

The critical questions that remain unanswered is whetherthe prolonged IFN-I response observed during pathogenicHIV-1SIV infection plays a determinant role in viral immu-nopathogenesis and whether pDC-mediated acute responsesor chronic IFN-I responses mediated by non-pDC subsetsare potentially valuable targets for immunotherapeutic orcurative interventions

33 Other Cellular Sources of IFN-I The broad expression ofRLR and cytosolicDNA sensors in numerous cell types and indifferent tissues [18] suggests that any cell susceptible to HIV-1 infection and therefore to cytoplasmic exposure of viralRNA has the potential to secrete IFN-120572 during HIV-1 infec-tion Nonetheless evidence about IFN-120572 production by cellsother than DC and monocytes is scattered and largely incon-clusive about its relevance for systemic immune activationand immunopathogenesis However IFN-120572-producing cellsubsets which are confided to specific anatomic locationsmaycontribute to inflammatory processes within non lymphoidtissues and organs partially accounting for the develop-ment of HIV-1-associated non-communicable comorbidities(NCCM)An increasing body of evidence suggests a causativelink between chronic inflammation and some manifestationsof NCCM One example is that of neurological complica-tions associatedwith neuroinflammationwhich are observedeven in patients in whom viral replication in controlled bycombination antiretroviral therapy (cART) [75ndash77] Thusmicroglial activation and an IFN-driven gene regulation sig-nature are characteristic ofHIV-associated neurological sym-ptoms such as cognitive impairment and depressive disorder[75 76 78 79] It is noteworthy that neurologic diseaseassociated with infection with another human lymphotropicretrovirus the human T-lymphotropic virus type 1 (HTLV-1) is also associated with an IFN-dominated inflamma-tory profile Thus Tattermusch and colleagues describedan IFN-inducible signature in HTLV-1-associated myelopa-thytropical spastic paraparesis (HAMTSP) [80 81] It is stillunclear whether peripheral sources of IFN-I such as DC ormacrophages are the sole responsible for the neuropathologiceffects or whether astrocytes and microglial cells are directlyinvolved in the production of IFN-I during the inflammatoryresponse Whether IFN-I production by these cells plays arole also in the immunopathogenesis of HIV-1 infection is yetto be determined

Scientifica 5

4 Effect of IFN-I on Target Cells

Type I IFN are the most potent natural mediators of antiviralactivity in humans The combination of proapoptotic andcytostatic activity as well as the direct induction of intracel-lular viral restriction factors contribute to generate a cellularenvironment which is unsuitable for viral replication [1 3 8283] The replication of HIV-1 is efficiently inhibited by IFN-I in vitro but the potential of IFN-I as antiretroviral agentsduring chronic HIV-1 infection in vivo is dubious [84ndash89]

IFN-I also contribute to the maturation of APC and exerta modulatory effect on different T cell subsets thereforeposing the foundations for promoting antigen-specific adap-tive immune responses and shaping them according to theinvading pathogen [1 6 7 53 82 90]

41 IFN-120572 Receptor Complex and Signalling The cellulareffects of IFN-I aremediated by the engagement of a commonreceptor complex the IFN-120572 receptor complex (IFNAR)which is expressed at different levels on the surface of virtuallyall human cells The IFNAR complex is a heterodimer of thetwo subunits IFNAR1 and IFNAR2 Human IFNAR1 com-prises an extracellular domain a transmembrane region andan intracellular domain of 100 amino acid residues Threedifferent forms of IFNAR2 have been described the fulllength receptor chain which includes a 250 residues cytoplas-mic portion an alternative form with a shorted intracellularportion (67 residues) [91 92] and a soluble form lackingthe transmembrane and cytoplasmic portions [91] HumanIFNAR2 binds all human IFN-I with higher affinity thanIFNAR1 but the affinity of the IFNAR heterodimer for mosthuman IFN-I is 10 fold higher than IFNAR2 alone [91 93 94]

The cytoplasmic domains of IFNAR1 and IFNAR2 areassociated with the tyrosine kinase (TYK)-2 and janus kin-ase (JAK)-1 respectively [91] Upon IFN-I binding to theIFNAR complex the tyrosine kinases are activated and orc-hestrate the signal transduction machinery [95] TYK-2and JAK-1 phosphorylate tyrosine residues on the IFNARand phosphorylated tyrosines act as docking sites for thesrc-homology-2 (SH2) domains of signal transducer andactivator of transcription (STAT) proteins which are thentargeted for phosphorylation [96 97] STAT1 STAT2 STAT3and STAT5 are expressed and activated by IFN-I in mostcell types whereas IFN-I-induced activation of STAT4 andSTAT6 is limited to lymphocytes [96 97]

STAT2 is recruited to the IFNAR1 cytoplasmic domainand is phosphorylated by TYK-2 serving as a lure for STAT1[98] which is also phosphorylated at tyrosine 701The STAT1-STAT2 heterodimer associates with the DNA binding proteininterferon regulatory factor 9 (IRF9) to form a signallingcomplex called IFN-stimulated gene factor-3 (ISGF3) TheISGF3 complex translocates to the nucleus where it promotesthe transcription of IFN-I-stimulated genes (ISG) by inter-acting with the IFN-stimulated response elements (ISRE)usually situated within 200 base pairs of the transcriptionstart site An additional phosphorilation of STAT1 at serine727 mediated by protein kinase C-120575 (PKC-120575) is essential forefficient transcriptional activity [1 98] In addition STAT1homodimers can bind to IFN-120574-activated site (GAS) in the

promoter region of IFN-I-stimulated genes [99 100] Thuswhile IFN-I can activate genes containing either ISRE or GASpromoter elements IFN-120574 is unable to induce the formationof ISGF3 and activate genes via ISRE [101] Signalling viaSTAT1-STAT2 is responsible for some of the most commonlyobserved effects of IFN-I during chronic HIV-1 infectionincluding the activation of proapoptotic and cytostatic genesviral restriction factors and immunomodulatory effects [102ndash104]

Type I IFN also triggers phosphorylation of STAT3[105] promoting its dimerization and migration to the nucl-eus STAT3 homodimers activate the transcription of genescontaining the enhancer sequence STAT3-binding element(SBE) Despite sharing high sequence similarity with STAT1STAT3 activation induces a gene expression profile distinctfrom that dependent on STAT1-STAT2 [106] including genesof the B cell lymphoma (BCL) family and the oncogeneMYC which promote proliferation and antagonize apoptosis[107 108] Furthermore STAT3 is responsible for the sup-pression of inflammatory responses via IL-10 which directlycounteracts STAT1 activity [109]

IFN-120573 also activates the signal transduction pathwaymediated by JAK1 and phosphoinositide 3-kinase (PI3K)leading to the expression of genes regulated by cyclic adeno-sine monophosphate (cAMP) via the nuclear translocation ofcAMP-responsive-element (CRE) binding protein (CREB)Similar to the STAT3-mediated pathway PI3K signalling canalso result in IL-10 production by DC [110] However thetwo pahways appear to be independent from each other Themammalian target of rapamycin (mTOR) is activated down-stream of the PI3K signalling cascade [111] Activation ofmTOR is independent of STAT signalling and does notmodify the gene expression profile but modulates mRNAtranslation by regulating the activation of p70 S6 kinase andthe phosphorylation of the ribosomal protein S6 [112 113]

The signalling pathway mediated by p38 mitogen-activ-ated protein kinases (p38-MAPK) and extracellular signal-regulated kinase (ERK) 1 or ERK2 is also activated by IFN-IThus genes which contain ISRE and GAS elements in theirpromoter region can be upregulated via a STAT-independentpathwaymediated by p38-MAPK [114ndash116] and the cytostaticand antiviral effects of IFN-I are dependent on intact p38-MAPK signalling machinery [117ndash120]

It is reasonable to expect that different IFN-I signaltransduction pathways are activated during HIV-1 infectionHowever the STAT1-STAT2 pathway is arguably the bestdescribed in the setting of IFN-I production during HIV-1 infection The activation of STAT proteins by HIV-1 wasdescribed in different experimental conditions involvingHIV-1-induced IFN-I production productive HIV-1 infec-tion of target cells or simple exposure to viral proteins Thusin vitro exposure of cell lines or primary leukocytes towhole HIV-1 virions was repeatedly shown to activate STAT-dependent pathways inCD4T cells and cells of themonocyticlineage [55 121 122] Interestingly Renga and colleaguesreported that exposure of monocytic cell lines to the HIV-1matrix protein p17 was sufficient to activate the JAK1STAT1axis and cause upregulation of STAT1 sensitive genes [123]suggesting that STAT1 activation during HIV-1 infectionmay

6 Scientifica

also occur independent of IFN-I production Simian immun-odeficiency virus (SIV) infection of nonhuman primates invivo resulted in upregulation of gene expression for STAT1STAT2 and IRF9 during the acute phase of infection whichwas protracted through the early chronic phase only indisease susceptible primate species not in disease resistantAfrican species [124 125] Although signalling via the ISGF3complex is regulated by post-transcriptional modification ofSTAT proteins not by modulation of STAT and IRF9 geneexpression the observed increases in the expression of thesemolecules in SIV-infectedmacaques [124 125] is indicative ofenhanced activity of the IFN-IISGF3 axis

The central role played by PI3K in multiple signal trans-duction pathways renders it difficult to distinguish its partici-pation in mediating the effects of IFN-I from other biochem-ical cellular and molecular events occurring during HIV-1infection The contribution of PI3K in neuroinflammationassociatedwithHIV-1 infection has been described [126ndash128]but the role of Pi3KmTOR in HIV-1 immunopathogenesisremains unclear

Activation of the p38-MAPK pathway during HIV-1 infe-ction has been described by several groups [129ndash139] How-ever studies on the p38-MAPKERK pathway have generallyfocused on the direct effect of HIV-1 gp120 singalling viaengagement of CD4 or the coreceptors CCR5 and CXCR4[129 136ndash139] rather than IFN-I production In particularactivation of p38-MAPKERK has been studied in referenceto its role in modulating cell activation and HIV-1 replication[129ndash135]

42 Expression Pattern of IFNAR Type I IFN are generallyconsidered to exert their biologic effect on virtually all humancells This broad and noncell specific activity reflects theprominent innate antiviral function of IFN-I which needs toreach any potential target of viral infection

However cell-specific differences in the responsivenessto IFN-I signalling have been observed in humans partic-ularly among immune effector cells Thus IFN-I inducingTLR9 agonists as well as HIV-1 efficiently upregulated theexpression of the IFN-I regulated gene PDL1 on primaryhuman monocytes and a subset of T lymphocytes identifiedby selective expression of the chemokine receptor CCR5 [21]Analysis of IFNAR2 expression in T lymphocytes revealedthat this subunit of IFNAR was almost exclusively restrictedto CCR5+ T cell subsets independent of whether CD4 orCD8 T cells were considered [21] A similar restriction ofIFN-I signalling to CCR5+ T cells was observed when HIV-1-induced upregulation of the T cell activationmarkers CD38and CD69 was analyzed in vitro [9 140]

In both humans and non-human primates CCR5 expres-sion is generally higher in memory and effector T cell subsets[141ndash144] and natural disease-resistant SIV host speciessuch as sooty mangabeys show reduced levels of CCR5+CD4 T cells compared to disease susceptible hosts such ashumans and Rhesus macaques [142 143] The role playedby CCR5 as coreceptor for HIV-1 and SIV Env proteinsproviding the critical mechanism for envelope-membranefusion and injection of the viral RNA into the cytoplasmprovided the basis for investigating how differences in CCR5

expression between different species translate into differenttransmission and disease progression phenotype [142 145]However little attention has been given to the possibility thatdifferent profiles of CCR5 expression among primate speciesmay account for different sensitivity to IFN-I production andtherefore different patterns of regulation of IFN-I-stimulatedgenes during chronic HIV-1 or SIV infection ultimatelyaccounting for differences in disease susceptibility

43 Cytostatic and Proapoptotic Effects Type I IFN are widelyrecognized as the most potent natural mediators of antiviralactivity in humans [1 3] Because the life cycle of viruses isdirectly influenced by the intracellular environment efficientantiviral mechanisms have developed to interfere with basiccellular functions or in an even more resolute mannereliminate infected cells which represent the factories ofviral replication These goals are achieved by IFN-I via theupregulation of genes exerting cytostatic and proapoptoticactivities The broadly effective antiviral mechanisms includethe induction of molecular mechanisms interfering with pro-tein synthesis and cellular activity as well as the stimulationof ligandreceptor-dependent apoptotic pathways and stressresponses While exerting potent antiretroviral activity thesemechanisms clearly interferewith basic cellular functions andcarry a potentially destructive risk for the host hence theneed for tight regulation of both the kinetic of activation andthe restriction to specific anatomical locations

During HIV-1 infection the chronic induction of IFN-Iresponses may contribute to progressive immunodeficiency[10 146]

431 Ligand-Receptor Mediated Apoptosis Type I IFN posi-tively regulates the expression of tumor necrosis factor (TNF)family members capable of inducing apoptosis in cells whichexpress specific receptors Thus expression of FAS ligand(FasL) TNF-related apoptosis inducing ligand (TRAIL) andprogrammed death ligand (PDL) 1 are all directly regulatedby IFN-I signalling [21 146ndash148]

The contribution of the FasFasL system to CD4 T cellapoptosis during HIV-1 infection is well documented [149ndash151] and similar findings were reported for IFN-I-inducedTRAIL and its death receptor (DR)5 [55 65 121 152 153]TRAIL expression following HIV-1 exposure or infection hasbeen described in T cells monocytes and pDC [24 55 153154] and TRAIL expressing pDChave been shown to directlyinduce apoptosis of CD4 T cells in HIV-1 infected patientswith high viraemia [153] TRAIL mediated apoptosis in thesetting of HIV-1 stimulation in vitro was originally reportedto affect CD4 T cells but not CD8 T cells [55 65 152]Interestingly TRAIL mediated CD4 T cell apoptosis did notrequire productive infection and TRAIL expressing pDCwere reported to be unable to lyse HIV-1 infected CD4 Tcells [155] possibly favouring the depletion of uninfectedCD4 T helper cells in the face of CD4 T cell viral reservoirspreservation However Zhu et al later described TRAILdependent apoptosis in HIV-1 infected macrophages as aresult of the downregulation of a decoy receptor [156]Thus TRIAL induced apoptosis may contribute to regulating

Scientifica 7

the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

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Scientifica 3

leading to production of the interleukin (IL)-6 TNF-120572IFN-120572 and IFN-120573 [41]The cellular sources of the proinflam-matory cytokines were not investigated in this study Itis plausible that during HIV-1 infection in vivo all cellssusceptible of infection have the potential to respond toHIV-1 genomic RNA via RIG-I sensing However the natureof the responses may differ depending on the target cellsand inflammatory responses may be differentially mediatedby DC and monocytemacrophages compared to CD4 Tlymphocytes

23 Cytoplasmic DNA Sensors The presence of a RNA-DNA hybrid during reverse transcription of the HIV-1 RNAgenome into dsDNA suggests that cytoplasmic recognition ofthe proviral DNA may occur before its translocation to thenucleus and integration into the host genome

The cytosol of eukaryotic cells is rich in enzymes withDNase activity which prevent accumulation of DNA in thecytoplasm [42] However when the preventive measuresexerted by cytoplasmic DNases fail DNA of viral originmay accumulate in the cytoplasm Double stranded DNAis a potent immune stimulator when present in the cytosolof target cells [43 44] and recent evidence indicates thatsingle-stranded DNA with specific signatures such as AT-rich regions is also a strong activator of immune responses[45] Sensing of cytoplasmic DNA triggers a cascade of signaltransduction orchestrated by the adaptormolecule stimulatorof interferon genes (STING) [46ndash49] leading to the produc-tion of proinflammatory and antiviral cytokines includingIFN-I [48] STING engages TBK1 to cause IRF3 activationand the STING-TBK1-IRF3 signaling axis is critical for IFN-Iinduction by cytosolic DNA [50]

Recent evidence indicates that cytosolic HIV-1-deriveddsDNA or RNADNA heterodimersmay trigger innate imm-une responses Gao and colleagues have used both themono-cytic cell line THP1 and primary human monocyte-derivedmacrophages and dendritic cells to show that HIV infectioninduces the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) which binds to andactivates STING resulting in the production of IFN-I [51]The production of IFN-120573 was strictly dependent on reversetranscription indicating that HIV-1 DNA acts as the initialtrigger for IFN-I production [51] Furthermore Jakobsen andcolleagues have shown that ssDNA generated from HIV-1proviral genome is a potent activator of IFN-I in primaryhumanmonocyte-derivedmacrophages [52] Single strandedHIV-1 DNA engages the IFN-inducible protein 16 (IFI16) inthe cytoplasmofmacrophages leading to the activation of theSTING-TBK1-IRF3 pathway [52]

3 Cellular Sources of IFN-I duringHIV-1 Infection

31 Plasmacytoid Dendritic Cells Plasmacytoid DC are themost potent producers of IFN-I in response to viral infections[16 53 54] Expression of endosomal TLR7 and TLR9 allowspDC to respond to both RNA and DNA viruses whichare engulfed and trafficked into the endosomal pathway

Upon TLR79 engagement pDC can mature into antigen-presenting cells (APC) or IFN-I-producing cells (IPC) andthe prevalence of one pathway over the other largely dependson the intracellular locale in which the TLR ligand triggers itsreceptor [23 39]Thus the engagement of TLR79 within theearly endosomes causes strong activation of the IRF7 pathwayvia an IFN-120572120573-dependent positive feedback resulting in theproduction of high quantities of IFN-120572 and pDC differen-tiation into IFN-I-producing cells (IPC) [39] Conversely ifthe TLR ligand is trafficked to the lysosomes or late endo-somes signal transduction via the NF-120581B pathway is favoredresulting in the upregulation of costimulatory molecules andmaturation into APC [39] OrsquoBrien and colleagues reportedthat HIV-1 is preferentially trafficked to the early endosomesof pDC which in turn promotes a persistently activated IPCstatus combined with partial or incomplete maturation [23]

The binding of the HIV-1 envelope glycoprotein gp120 toCD4 but not to the coreceptors CCR5 or CXCR4 is requiredfor virion engulfment and subsequent activation of pDC viaTLR7 engagement [12 55] The interaction between gp120and CD4 is stabilized by accessory interactions involvingcellular adhesion molecules on both the cell membrane andviral envelope allowing the formation of a stable bindinginterface between HIV-1 and the target cells [56ndash58] Thusthe envelope of newly formed HIV-1 virions incorporatescellular proteins derived from the host cell of origin [5657 59] these cell-derived proteins contribute to virus-cellinteractions and may modulate the dynamics of infectionof target cells and uptake by endocytotic cells [57ndash60] Inaddition the HIV-1 envelope is not homogenous but ratherorganized in a functional substructure enriched in tightlypacked cholesterol similar to the lipid rafts described ineukaryotic cells including human leukocytes [9 60 61] Theorganization of a functional virion-associated lipid raft isrequired to confer HIV-1 the ability to induce potent IFN-Iproduction via pDC stimulation [9] Thus the efficiency ofHIV-1 uptake by pDC and the potency of IFN-I inductionare strongly reduced if envelope-associated cholesterol iswithdrawn by chemical treatment [9] However cholesteroldepleted HIV-1 partially retains the ability to promote pDCmaturation into APC [9] suggesting that the integrity of thevirion-associated lipid raftmay not only reduce the efficiencyof HIV-1 uptake but also modify the dynamics of HIV-1trafficking and subsequent TLR signalling in favour NF-120581B-mediated APCmaturation rather than IRF7-dependent IFN-120572 production

Activation of pDCmayoccurwithin hours fromexposureto HIV-1 in vivo Intravaginal infection of rhesus macaquescaused rapid accumulation of activated pDC at the mucosalsite of infection which resulted inmacrophage inflammatoryprotein (MIP)-3120572-mediated chemoattraction and infectionof CCR5-expressing CD4 T cells contributing to the spreadof the infection to secondary lymphoid tissues [62] LubongSabado and colleagues reported that pDC relocate to lym-phoid tissues already during primary HIV-1 infection a con-dition which persists throughout the course of disease [63]However reports on IFN-120572 secretion by pDC in lymphoidtissues during chronic HIV-1 infection showed contrastingresults For example although IFN-120572 and upregulation of

4 Scientifica

IFN-stimulated genes (ISG) has been reported in tissues fromHIV+ patients [64 65] Nascimbeni and colleagues showedthat pDC in the spleen of HIV-infected patients have animmature phenotype and do not contribute to the increasedIFN-120572 production [66] The state of partial or incompletepDCmaturation is confirmed in the study by Benlahrech andcolleagues who have recently shown that expression of theimmunoglobulin-like transcript (ILT) 7 a regulatory receptorexpressed by immature circulating pDC but not partiallydifferentiated cells [36] is reduced in pDC fromHIV-infectedpatients when viral replication is not efficiently controlled bytherapy [67]

Recent evidence suggests that pDC may be the predo-minant source of IFN-I only during the initial phases ofacute infection whereas mDC and macrophages becomeimportant producers of IFN-120572 when the course of infectiontransitions to the early chronic phase [13] Both mDC andmonocytemacrophages express TLR8 which has the poten-tial to recognize viral RNA [68 69] However several studieshave shown that in vitromaturation ofmDCandmonocyte inpresence of HIV-1 is a bystander effect occurring in responseto cytokines produced by HIV-1-activated pDC such as IFN-120572 and TNF-120572 [12 21ndash23] In addition even in conditionsin which TLR8 engagement occurs mDC do not respondby secreting IFN-I but rather mature into interleukin (IL)-12-secreting APC [68 69] Thus IFN-I production by mDCand macrophages during the post-acute and chronic phasesof HIV-1 infection may depend on molecular pathwaysother than sensing of extracellular viral particles virus viaendosomal TLR

32 MonocytesMacrophages and Myeloid Dendritic CellsEndosomal TLR allow recognition of nucleic acids fromviruses engulfed by specialized cells but may not senseviral genomes which have gained access to the cytoplasmIntracellular RLR and DNA sensors are triggered by viralgenome in the cytoplasm and induce the production ofantiviral and immunostimulatory cytokines such as IFN-120572and TNF-120572 [18] RLR are expressed by most cell types andtheir triggering requires that the viral genome has reachedthe cytoplasm a condition which is also necessary to achieveproductive infection of the target cell Conversely TLR79-mediated pDC responses would not be triggered during aproductive infectious cycle due to the segregation of thereceptors in the endosomal compartmentThismay representa critical difference between IFN-I responses orchestrated byuninfected pDC during the early phases of viral exposure andIFN-I production by productively infected cells during laterstages of infection

This transition from a pDC-mediated to an apparen-tly pDC-independent IFN-I response has been recently des-cribed in the HIV-1 simian model of simian immunodefi-ciency infection (SIV) of Rhesus macaques by Kader andcolleagues [13] Monocyte derived macrophages have beenshown to respond to HIV-1 proviral DNA via intracellularDNA sensors [51 52] and genomic HIV-1 RNA activatesinnate immune responses in peripheralmononuclear cells viaRLR [41] The question can be raised as to whether the mainsource of IFN-I changes during HIV-1 infection in relation

to a shift in the distribution of productively infected cellsamong different cell types Dendritic cells may act as catalystsfor the infection of CD4 T cells via cell-cell transfer [70 71]but activated CCR5+ CD4 T cells are the main target forinfection and the main source of viral replication throughoutthe acute phase [72 73] However the number of CCR5+ Tcells decreases progressively during acute infection both inthe periphery and in lymphoid tissues likely due to a com-bination of viral cytotoxicity activation-induced apoptosisand immune-dependent killing mediated by newly activatedHIV-1-specific cytotoxic CD8 T lymphocytes (CTL) [72ndash74]Thus as the pool of CCR5+ CD4 T cells decreases CD4-expressing mDC and monocytemacrophages may becomeincreasinglymore important as targets for infection and ther-efore more susceptible to activation via cytoplasmic RLR

The critical questions that remain unanswered is whetherthe prolonged IFN-I response observed during pathogenicHIV-1SIV infection plays a determinant role in viral immu-nopathogenesis and whether pDC-mediated acute responsesor chronic IFN-I responses mediated by non-pDC subsetsare potentially valuable targets for immunotherapeutic orcurative interventions

33 Other Cellular Sources of IFN-I The broad expression ofRLR and cytosolicDNA sensors in numerous cell types and indifferent tissues [18] suggests that any cell susceptible to HIV-1 infection and therefore to cytoplasmic exposure of viralRNA has the potential to secrete IFN-120572 during HIV-1 infec-tion Nonetheless evidence about IFN-120572 production by cellsother than DC and monocytes is scattered and largely incon-clusive about its relevance for systemic immune activationand immunopathogenesis However IFN-120572-producing cellsubsets which are confided to specific anatomic locationsmaycontribute to inflammatory processes within non lymphoidtissues and organs partially accounting for the develop-ment of HIV-1-associated non-communicable comorbidities(NCCM)An increasing body of evidence suggests a causativelink between chronic inflammation and some manifestationsof NCCM One example is that of neurological complica-tions associatedwith neuroinflammationwhich are observedeven in patients in whom viral replication in controlled bycombination antiretroviral therapy (cART) [75ndash77] Thusmicroglial activation and an IFN-driven gene regulation sig-nature are characteristic ofHIV-associated neurological sym-ptoms such as cognitive impairment and depressive disorder[75 76 78 79] It is noteworthy that neurologic diseaseassociated with infection with another human lymphotropicretrovirus the human T-lymphotropic virus type 1 (HTLV-1) is also associated with an IFN-dominated inflamma-tory profile Thus Tattermusch and colleagues describedan IFN-inducible signature in HTLV-1-associated myelopa-thytropical spastic paraparesis (HAMTSP) [80 81] It is stillunclear whether peripheral sources of IFN-I such as DC ormacrophages are the sole responsible for the neuropathologiceffects or whether astrocytes and microglial cells are directlyinvolved in the production of IFN-I during the inflammatoryresponse Whether IFN-I production by these cells plays arole also in the immunopathogenesis of HIV-1 infection is yetto be determined

Scientifica 5

4 Effect of IFN-I on Target Cells

Type I IFN are the most potent natural mediators of antiviralactivity in humans The combination of proapoptotic andcytostatic activity as well as the direct induction of intracel-lular viral restriction factors contribute to generate a cellularenvironment which is unsuitable for viral replication [1 3 8283] The replication of HIV-1 is efficiently inhibited by IFN-I in vitro but the potential of IFN-I as antiretroviral agentsduring chronic HIV-1 infection in vivo is dubious [84ndash89]

IFN-I also contribute to the maturation of APC and exerta modulatory effect on different T cell subsets thereforeposing the foundations for promoting antigen-specific adap-tive immune responses and shaping them according to theinvading pathogen [1 6 7 53 82 90]

41 IFN-120572 Receptor Complex and Signalling The cellulareffects of IFN-I aremediated by the engagement of a commonreceptor complex the IFN-120572 receptor complex (IFNAR)which is expressed at different levels on the surface of virtuallyall human cells The IFNAR complex is a heterodimer of thetwo subunits IFNAR1 and IFNAR2 Human IFNAR1 com-prises an extracellular domain a transmembrane region andan intracellular domain of 100 amino acid residues Threedifferent forms of IFNAR2 have been described the fulllength receptor chain which includes a 250 residues cytoplas-mic portion an alternative form with a shorted intracellularportion (67 residues) [91 92] and a soluble form lackingthe transmembrane and cytoplasmic portions [91] HumanIFNAR2 binds all human IFN-I with higher affinity thanIFNAR1 but the affinity of the IFNAR heterodimer for mosthuman IFN-I is 10 fold higher than IFNAR2 alone [91 93 94]

The cytoplasmic domains of IFNAR1 and IFNAR2 areassociated with the tyrosine kinase (TYK)-2 and janus kin-ase (JAK)-1 respectively [91] Upon IFN-I binding to theIFNAR complex the tyrosine kinases are activated and orc-hestrate the signal transduction machinery [95] TYK-2and JAK-1 phosphorylate tyrosine residues on the IFNARand phosphorylated tyrosines act as docking sites for thesrc-homology-2 (SH2) domains of signal transducer andactivator of transcription (STAT) proteins which are thentargeted for phosphorylation [96 97] STAT1 STAT2 STAT3and STAT5 are expressed and activated by IFN-I in mostcell types whereas IFN-I-induced activation of STAT4 andSTAT6 is limited to lymphocytes [96 97]

STAT2 is recruited to the IFNAR1 cytoplasmic domainand is phosphorylated by TYK-2 serving as a lure for STAT1[98] which is also phosphorylated at tyrosine 701The STAT1-STAT2 heterodimer associates with the DNA binding proteininterferon regulatory factor 9 (IRF9) to form a signallingcomplex called IFN-stimulated gene factor-3 (ISGF3) TheISGF3 complex translocates to the nucleus where it promotesthe transcription of IFN-I-stimulated genes (ISG) by inter-acting with the IFN-stimulated response elements (ISRE)usually situated within 200 base pairs of the transcriptionstart site An additional phosphorilation of STAT1 at serine727 mediated by protein kinase C-120575 (PKC-120575) is essential forefficient transcriptional activity [1 98] In addition STAT1homodimers can bind to IFN-120574-activated site (GAS) in the

promoter region of IFN-I-stimulated genes [99 100] Thuswhile IFN-I can activate genes containing either ISRE or GASpromoter elements IFN-120574 is unable to induce the formationof ISGF3 and activate genes via ISRE [101] Signalling viaSTAT1-STAT2 is responsible for some of the most commonlyobserved effects of IFN-I during chronic HIV-1 infectionincluding the activation of proapoptotic and cytostatic genesviral restriction factors and immunomodulatory effects [102ndash104]

Type I IFN also triggers phosphorylation of STAT3[105] promoting its dimerization and migration to the nucl-eus STAT3 homodimers activate the transcription of genescontaining the enhancer sequence STAT3-binding element(SBE) Despite sharing high sequence similarity with STAT1STAT3 activation induces a gene expression profile distinctfrom that dependent on STAT1-STAT2 [106] including genesof the B cell lymphoma (BCL) family and the oncogeneMYC which promote proliferation and antagonize apoptosis[107 108] Furthermore STAT3 is responsible for the sup-pression of inflammatory responses via IL-10 which directlycounteracts STAT1 activity [109]

IFN-120573 also activates the signal transduction pathwaymediated by JAK1 and phosphoinositide 3-kinase (PI3K)leading to the expression of genes regulated by cyclic adeno-sine monophosphate (cAMP) via the nuclear translocation ofcAMP-responsive-element (CRE) binding protein (CREB)Similar to the STAT3-mediated pathway PI3K signalling canalso result in IL-10 production by DC [110] However thetwo pahways appear to be independent from each other Themammalian target of rapamycin (mTOR) is activated down-stream of the PI3K signalling cascade [111] Activation ofmTOR is independent of STAT signalling and does notmodify the gene expression profile but modulates mRNAtranslation by regulating the activation of p70 S6 kinase andthe phosphorylation of the ribosomal protein S6 [112 113]

The signalling pathway mediated by p38 mitogen-activ-ated protein kinases (p38-MAPK) and extracellular signal-regulated kinase (ERK) 1 or ERK2 is also activated by IFN-IThus genes which contain ISRE and GAS elements in theirpromoter region can be upregulated via a STAT-independentpathwaymediated by p38-MAPK [114ndash116] and the cytostaticand antiviral effects of IFN-I are dependent on intact p38-MAPK signalling machinery [117ndash120]

It is reasonable to expect that different IFN-I signaltransduction pathways are activated during HIV-1 infectionHowever the STAT1-STAT2 pathway is arguably the bestdescribed in the setting of IFN-I production during HIV-1 infection The activation of STAT proteins by HIV-1 wasdescribed in different experimental conditions involvingHIV-1-induced IFN-I production productive HIV-1 infec-tion of target cells or simple exposure to viral proteins Thusin vitro exposure of cell lines or primary leukocytes towhole HIV-1 virions was repeatedly shown to activate STAT-dependent pathways inCD4T cells and cells of themonocyticlineage [55 121 122] Interestingly Renga and colleaguesreported that exposure of monocytic cell lines to the HIV-1matrix protein p17 was sufficient to activate the JAK1STAT1axis and cause upregulation of STAT1 sensitive genes [123]suggesting that STAT1 activation during HIV-1 infectionmay

6 Scientifica

also occur independent of IFN-I production Simian immun-odeficiency virus (SIV) infection of nonhuman primates invivo resulted in upregulation of gene expression for STAT1STAT2 and IRF9 during the acute phase of infection whichwas protracted through the early chronic phase only indisease susceptible primate species not in disease resistantAfrican species [124 125] Although signalling via the ISGF3complex is regulated by post-transcriptional modification ofSTAT proteins not by modulation of STAT and IRF9 geneexpression the observed increases in the expression of thesemolecules in SIV-infectedmacaques [124 125] is indicative ofenhanced activity of the IFN-IISGF3 axis

The central role played by PI3K in multiple signal trans-duction pathways renders it difficult to distinguish its partici-pation in mediating the effects of IFN-I from other biochem-ical cellular and molecular events occurring during HIV-1infection The contribution of PI3K in neuroinflammationassociatedwithHIV-1 infection has been described [126ndash128]but the role of Pi3KmTOR in HIV-1 immunopathogenesisremains unclear

Activation of the p38-MAPK pathway during HIV-1 infe-ction has been described by several groups [129ndash139] How-ever studies on the p38-MAPKERK pathway have generallyfocused on the direct effect of HIV-1 gp120 singalling viaengagement of CD4 or the coreceptors CCR5 and CXCR4[129 136ndash139] rather than IFN-I production In particularactivation of p38-MAPKERK has been studied in referenceto its role in modulating cell activation and HIV-1 replication[129ndash135]

42 Expression Pattern of IFNAR Type I IFN are generallyconsidered to exert their biologic effect on virtually all humancells This broad and noncell specific activity reflects theprominent innate antiviral function of IFN-I which needs toreach any potential target of viral infection

However cell-specific differences in the responsivenessto IFN-I signalling have been observed in humans partic-ularly among immune effector cells Thus IFN-I inducingTLR9 agonists as well as HIV-1 efficiently upregulated theexpression of the IFN-I regulated gene PDL1 on primaryhuman monocytes and a subset of T lymphocytes identifiedby selective expression of the chemokine receptor CCR5 [21]Analysis of IFNAR2 expression in T lymphocytes revealedthat this subunit of IFNAR was almost exclusively restrictedto CCR5+ T cell subsets independent of whether CD4 orCD8 T cells were considered [21] A similar restriction ofIFN-I signalling to CCR5+ T cells was observed when HIV-1-induced upregulation of the T cell activationmarkers CD38and CD69 was analyzed in vitro [9 140]

In both humans and non-human primates CCR5 expres-sion is generally higher in memory and effector T cell subsets[141ndash144] and natural disease-resistant SIV host speciessuch as sooty mangabeys show reduced levels of CCR5+CD4 T cells compared to disease susceptible hosts such ashumans and Rhesus macaques [142 143] The role playedby CCR5 as coreceptor for HIV-1 and SIV Env proteinsproviding the critical mechanism for envelope-membranefusion and injection of the viral RNA into the cytoplasmprovided the basis for investigating how differences in CCR5

expression between different species translate into differenttransmission and disease progression phenotype [142 145]However little attention has been given to the possibility thatdifferent profiles of CCR5 expression among primate speciesmay account for different sensitivity to IFN-I production andtherefore different patterns of regulation of IFN-I-stimulatedgenes during chronic HIV-1 or SIV infection ultimatelyaccounting for differences in disease susceptibility

43 Cytostatic and Proapoptotic Effects Type I IFN are widelyrecognized as the most potent natural mediators of antiviralactivity in humans [1 3] Because the life cycle of viruses isdirectly influenced by the intracellular environment efficientantiviral mechanisms have developed to interfere with basiccellular functions or in an even more resolute mannereliminate infected cells which represent the factories ofviral replication These goals are achieved by IFN-I via theupregulation of genes exerting cytostatic and proapoptoticactivities The broadly effective antiviral mechanisms includethe induction of molecular mechanisms interfering with pro-tein synthesis and cellular activity as well as the stimulationof ligandreceptor-dependent apoptotic pathways and stressresponses While exerting potent antiretroviral activity thesemechanisms clearly interferewith basic cellular functions andcarry a potentially destructive risk for the host hence theneed for tight regulation of both the kinetic of activation andthe restriction to specific anatomical locations

During HIV-1 infection the chronic induction of IFN-Iresponses may contribute to progressive immunodeficiency[10 146]

431 Ligand-Receptor Mediated Apoptosis Type I IFN posi-tively regulates the expression of tumor necrosis factor (TNF)family members capable of inducing apoptosis in cells whichexpress specific receptors Thus expression of FAS ligand(FasL) TNF-related apoptosis inducing ligand (TRAIL) andprogrammed death ligand (PDL) 1 are all directly regulatedby IFN-I signalling [21 146ndash148]

The contribution of the FasFasL system to CD4 T cellapoptosis during HIV-1 infection is well documented [149ndash151] and similar findings were reported for IFN-I-inducedTRAIL and its death receptor (DR)5 [55 65 121 152 153]TRAIL expression following HIV-1 exposure or infection hasbeen described in T cells monocytes and pDC [24 55 153154] and TRAIL expressing pDChave been shown to directlyinduce apoptosis of CD4 T cells in HIV-1 infected patientswith high viraemia [153] TRAIL mediated apoptosis in thesetting of HIV-1 stimulation in vitro was originally reportedto affect CD4 T cells but not CD8 T cells [55 65 152]Interestingly TRAIL mediated CD4 T cell apoptosis did notrequire productive infection and TRAIL expressing pDCwere reported to be unable to lyse HIV-1 infected CD4 Tcells [155] possibly favouring the depletion of uninfectedCD4 T helper cells in the face of CD4 T cell viral reservoirspreservation However Zhu et al later described TRAILdependent apoptosis in HIV-1 infected macrophages as aresult of the downregulation of a decoy receptor [156]Thus TRIAL induced apoptosis may contribute to regulating

Scientifica 7

the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

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[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 Scientifica

IFN-stimulated genes (ISG) has been reported in tissues fromHIV+ patients [64 65] Nascimbeni and colleagues showedthat pDC in the spleen of HIV-infected patients have animmature phenotype and do not contribute to the increasedIFN-120572 production [66] The state of partial or incompletepDCmaturation is confirmed in the study by Benlahrech andcolleagues who have recently shown that expression of theimmunoglobulin-like transcript (ILT) 7 a regulatory receptorexpressed by immature circulating pDC but not partiallydifferentiated cells [36] is reduced in pDC fromHIV-infectedpatients when viral replication is not efficiently controlled bytherapy [67]

Recent evidence suggests that pDC may be the predo-minant source of IFN-I only during the initial phases ofacute infection whereas mDC and macrophages becomeimportant producers of IFN-120572 when the course of infectiontransitions to the early chronic phase [13] Both mDC andmonocytemacrophages express TLR8 which has the poten-tial to recognize viral RNA [68 69] However several studieshave shown that in vitromaturation ofmDCandmonocyte inpresence of HIV-1 is a bystander effect occurring in responseto cytokines produced by HIV-1-activated pDC such as IFN-120572 and TNF-120572 [12 21ndash23] In addition even in conditionsin which TLR8 engagement occurs mDC do not respondby secreting IFN-I but rather mature into interleukin (IL)-12-secreting APC [68 69] Thus IFN-I production by mDCand macrophages during the post-acute and chronic phasesof HIV-1 infection may depend on molecular pathwaysother than sensing of extracellular viral particles virus viaendosomal TLR

32 MonocytesMacrophages and Myeloid Dendritic CellsEndosomal TLR allow recognition of nucleic acids fromviruses engulfed by specialized cells but may not senseviral genomes which have gained access to the cytoplasmIntracellular RLR and DNA sensors are triggered by viralgenome in the cytoplasm and induce the production ofantiviral and immunostimulatory cytokines such as IFN-120572and TNF-120572 [18] RLR are expressed by most cell types andtheir triggering requires that the viral genome has reachedthe cytoplasm a condition which is also necessary to achieveproductive infection of the target cell Conversely TLR79-mediated pDC responses would not be triggered during aproductive infectious cycle due to the segregation of thereceptors in the endosomal compartmentThismay representa critical difference between IFN-I responses orchestrated byuninfected pDC during the early phases of viral exposure andIFN-I production by productively infected cells during laterstages of infection

This transition from a pDC-mediated to an apparen-tly pDC-independent IFN-I response has been recently des-cribed in the HIV-1 simian model of simian immunodefi-ciency infection (SIV) of Rhesus macaques by Kader andcolleagues [13] Monocyte derived macrophages have beenshown to respond to HIV-1 proviral DNA via intracellularDNA sensors [51 52] and genomic HIV-1 RNA activatesinnate immune responses in peripheralmononuclear cells viaRLR [41] The question can be raised as to whether the mainsource of IFN-I changes during HIV-1 infection in relation

to a shift in the distribution of productively infected cellsamong different cell types Dendritic cells may act as catalystsfor the infection of CD4 T cells via cell-cell transfer [70 71]but activated CCR5+ CD4 T cells are the main target forinfection and the main source of viral replication throughoutthe acute phase [72 73] However the number of CCR5+ Tcells decreases progressively during acute infection both inthe periphery and in lymphoid tissues likely due to a com-bination of viral cytotoxicity activation-induced apoptosisand immune-dependent killing mediated by newly activatedHIV-1-specific cytotoxic CD8 T lymphocytes (CTL) [72ndash74]Thus as the pool of CCR5+ CD4 T cells decreases CD4-expressing mDC and monocytemacrophages may becomeincreasinglymore important as targets for infection and ther-efore more susceptible to activation via cytoplasmic RLR

The critical questions that remain unanswered is whetherthe prolonged IFN-I response observed during pathogenicHIV-1SIV infection plays a determinant role in viral immu-nopathogenesis and whether pDC-mediated acute responsesor chronic IFN-I responses mediated by non-pDC subsetsare potentially valuable targets for immunotherapeutic orcurative interventions

33 Other Cellular Sources of IFN-I The broad expression ofRLR and cytosolicDNA sensors in numerous cell types and indifferent tissues [18] suggests that any cell susceptible to HIV-1 infection and therefore to cytoplasmic exposure of viralRNA has the potential to secrete IFN-120572 during HIV-1 infec-tion Nonetheless evidence about IFN-120572 production by cellsother than DC and monocytes is scattered and largely incon-clusive about its relevance for systemic immune activationand immunopathogenesis However IFN-120572-producing cellsubsets which are confided to specific anatomic locationsmaycontribute to inflammatory processes within non lymphoidtissues and organs partially accounting for the develop-ment of HIV-1-associated non-communicable comorbidities(NCCM)An increasing body of evidence suggests a causativelink between chronic inflammation and some manifestationsof NCCM One example is that of neurological complica-tions associatedwith neuroinflammationwhich are observedeven in patients in whom viral replication in controlled bycombination antiretroviral therapy (cART) [75ndash77] Thusmicroglial activation and an IFN-driven gene regulation sig-nature are characteristic ofHIV-associated neurological sym-ptoms such as cognitive impairment and depressive disorder[75 76 78 79] It is noteworthy that neurologic diseaseassociated with infection with another human lymphotropicretrovirus the human T-lymphotropic virus type 1 (HTLV-1) is also associated with an IFN-dominated inflamma-tory profile Thus Tattermusch and colleagues describedan IFN-inducible signature in HTLV-1-associated myelopa-thytropical spastic paraparesis (HAMTSP) [80 81] It is stillunclear whether peripheral sources of IFN-I such as DC ormacrophages are the sole responsible for the neuropathologiceffects or whether astrocytes and microglial cells are directlyinvolved in the production of IFN-I during the inflammatoryresponse Whether IFN-I production by these cells plays arole also in the immunopathogenesis of HIV-1 infection is yetto be determined

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4 Effect of IFN-I on Target Cells

Type I IFN are the most potent natural mediators of antiviralactivity in humans The combination of proapoptotic andcytostatic activity as well as the direct induction of intracel-lular viral restriction factors contribute to generate a cellularenvironment which is unsuitable for viral replication [1 3 8283] The replication of HIV-1 is efficiently inhibited by IFN-I in vitro but the potential of IFN-I as antiretroviral agentsduring chronic HIV-1 infection in vivo is dubious [84ndash89]

IFN-I also contribute to the maturation of APC and exerta modulatory effect on different T cell subsets thereforeposing the foundations for promoting antigen-specific adap-tive immune responses and shaping them according to theinvading pathogen [1 6 7 53 82 90]

41 IFN-120572 Receptor Complex and Signalling The cellulareffects of IFN-I aremediated by the engagement of a commonreceptor complex the IFN-120572 receptor complex (IFNAR)which is expressed at different levels on the surface of virtuallyall human cells The IFNAR complex is a heterodimer of thetwo subunits IFNAR1 and IFNAR2 Human IFNAR1 com-prises an extracellular domain a transmembrane region andan intracellular domain of 100 amino acid residues Threedifferent forms of IFNAR2 have been described the fulllength receptor chain which includes a 250 residues cytoplas-mic portion an alternative form with a shorted intracellularportion (67 residues) [91 92] and a soluble form lackingthe transmembrane and cytoplasmic portions [91] HumanIFNAR2 binds all human IFN-I with higher affinity thanIFNAR1 but the affinity of the IFNAR heterodimer for mosthuman IFN-I is 10 fold higher than IFNAR2 alone [91 93 94]

The cytoplasmic domains of IFNAR1 and IFNAR2 areassociated with the tyrosine kinase (TYK)-2 and janus kin-ase (JAK)-1 respectively [91] Upon IFN-I binding to theIFNAR complex the tyrosine kinases are activated and orc-hestrate the signal transduction machinery [95] TYK-2and JAK-1 phosphorylate tyrosine residues on the IFNARand phosphorylated tyrosines act as docking sites for thesrc-homology-2 (SH2) domains of signal transducer andactivator of transcription (STAT) proteins which are thentargeted for phosphorylation [96 97] STAT1 STAT2 STAT3and STAT5 are expressed and activated by IFN-I in mostcell types whereas IFN-I-induced activation of STAT4 andSTAT6 is limited to lymphocytes [96 97]

STAT2 is recruited to the IFNAR1 cytoplasmic domainand is phosphorylated by TYK-2 serving as a lure for STAT1[98] which is also phosphorylated at tyrosine 701The STAT1-STAT2 heterodimer associates with the DNA binding proteininterferon regulatory factor 9 (IRF9) to form a signallingcomplex called IFN-stimulated gene factor-3 (ISGF3) TheISGF3 complex translocates to the nucleus where it promotesthe transcription of IFN-I-stimulated genes (ISG) by inter-acting with the IFN-stimulated response elements (ISRE)usually situated within 200 base pairs of the transcriptionstart site An additional phosphorilation of STAT1 at serine727 mediated by protein kinase C-120575 (PKC-120575) is essential forefficient transcriptional activity [1 98] In addition STAT1homodimers can bind to IFN-120574-activated site (GAS) in the

promoter region of IFN-I-stimulated genes [99 100] Thuswhile IFN-I can activate genes containing either ISRE or GASpromoter elements IFN-120574 is unable to induce the formationof ISGF3 and activate genes via ISRE [101] Signalling viaSTAT1-STAT2 is responsible for some of the most commonlyobserved effects of IFN-I during chronic HIV-1 infectionincluding the activation of proapoptotic and cytostatic genesviral restriction factors and immunomodulatory effects [102ndash104]

Type I IFN also triggers phosphorylation of STAT3[105] promoting its dimerization and migration to the nucl-eus STAT3 homodimers activate the transcription of genescontaining the enhancer sequence STAT3-binding element(SBE) Despite sharing high sequence similarity with STAT1STAT3 activation induces a gene expression profile distinctfrom that dependent on STAT1-STAT2 [106] including genesof the B cell lymphoma (BCL) family and the oncogeneMYC which promote proliferation and antagonize apoptosis[107 108] Furthermore STAT3 is responsible for the sup-pression of inflammatory responses via IL-10 which directlycounteracts STAT1 activity [109]

IFN-120573 also activates the signal transduction pathwaymediated by JAK1 and phosphoinositide 3-kinase (PI3K)leading to the expression of genes regulated by cyclic adeno-sine monophosphate (cAMP) via the nuclear translocation ofcAMP-responsive-element (CRE) binding protein (CREB)Similar to the STAT3-mediated pathway PI3K signalling canalso result in IL-10 production by DC [110] However thetwo pahways appear to be independent from each other Themammalian target of rapamycin (mTOR) is activated down-stream of the PI3K signalling cascade [111] Activation ofmTOR is independent of STAT signalling and does notmodify the gene expression profile but modulates mRNAtranslation by regulating the activation of p70 S6 kinase andthe phosphorylation of the ribosomal protein S6 [112 113]

The signalling pathway mediated by p38 mitogen-activ-ated protein kinases (p38-MAPK) and extracellular signal-regulated kinase (ERK) 1 or ERK2 is also activated by IFN-IThus genes which contain ISRE and GAS elements in theirpromoter region can be upregulated via a STAT-independentpathwaymediated by p38-MAPK [114ndash116] and the cytostaticand antiviral effects of IFN-I are dependent on intact p38-MAPK signalling machinery [117ndash120]

It is reasonable to expect that different IFN-I signaltransduction pathways are activated during HIV-1 infectionHowever the STAT1-STAT2 pathway is arguably the bestdescribed in the setting of IFN-I production during HIV-1 infection The activation of STAT proteins by HIV-1 wasdescribed in different experimental conditions involvingHIV-1-induced IFN-I production productive HIV-1 infec-tion of target cells or simple exposure to viral proteins Thusin vitro exposure of cell lines or primary leukocytes towhole HIV-1 virions was repeatedly shown to activate STAT-dependent pathways inCD4T cells and cells of themonocyticlineage [55 121 122] Interestingly Renga and colleaguesreported that exposure of monocytic cell lines to the HIV-1matrix protein p17 was sufficient to activate the JAK1STAT1axis and cause upregulation of STAT1 sensitive genes [123]suggesting that STAT1 activation during HIV-1 infectionmay

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also occur independent of IFN-I production Simian immun-odeficiency virus (SIV) infection of nonhuman primates invivo resulted in upregulation of gene expression for STAT1STAT2 and IRF9 during the acute phase of infection whichwas protracted through the early chronic phase only indisease susceptible primate species not in disease resistantAfrican species [124 125] Although signalling via the ISGF3complex is regulated by post-transcriptional modification ofSTAT proteins not by modulation of STAT and IRF9 geneexpression the observed increases in the expression of thesemolecules in SIV-infectedmacaques [124 125] is indicative ofenhanced activity of the IFN-IISGF3 axis

The central role played by PI3K in multiple signal trans-duction pathways renders it difficult to distinguish its partici-pation in mediating the effects of IFN-I from other biochem-ical cellular and molecular events occurring during HIV-1infection The contribution of PI3K in neuroinflammationassociatedwithHIV-1 infection has been described [126ndash128]but the role of Pi3KmTOR in HIV-1 immunopathogenesisremains unclear

Activation of the p38-MAPK pathway during HIV-1 infe-ction has been described by several groups [129ndash139] How-ever studies on the p38-MAPKERK pathway have generallyfocused on the direct effect of HIV-1 gp120 singalling viaengagement of CD4 or the coreceptors CCR5 and CXCR4[129 136ndash139] rather than IFN-I production In particularactivation of p38-MAPKERK has been studied in referenceto its role in modulating cell activation and HIV-1 replication[129ndash135]

42 Expression Pattern of IFNAR Type I IFN are generallyconsidered to exert their biologic effect on virtually all humancells This broad and noncell specific activity reflects theprominent innate antiviral function of IFN-I which needs toreach any potential target of viral infection

However cell-specific differences in the responsivenessto IFN-I signalling have been observed in humans partic-ularly among immune effector cells Thus IFN-I inducingTLR9 agonists as well as HIV-1 efficiently upregulated theexpression of the IFN-I regulated gene PDL1 on primaryhuman monocytes and a subset of T lymphocytes identifiedby selective expression of the chemokine receptor CCR5 [21]Analysis of IFNAR2 expression in T lymphocytes revealedthat this subunit of IFNAR was almost exclusively restrictedto CCR5+ T cell subsets independent of whether CD4 orCD8 T cells were considered [21] A similar restriction ofIFN-I signalling to CCR5+ T cells was observed when HIV-1-induced upregulation of the T cell activationmarkers CD38and CD69 was analyzed in vitro [9 140]

In both humans and non-human primates CCR5 expres-sion is generally higher in memory and effector T cell subsets[141ndash144] and natural disease-resistant SIV host speciessuch as sooty mangabeys show reduced levels of CCR5+CD4 T cells compared to disease susceptible hosts such ashumans and Rhesus macaques [142 143] The role playedby CCR5 as coreceptor for HIV-1 and SIV Env proteinsproviding the critical mechanism for envelope-membranefusion and injection of the viral RNA into the cytoplasmprovided the basis for investigating how differences in CCR5

expression between different species translate into differenttransmission and disease progression phenotype [142 145]However little attention has been given to the possibility thatdifferent profiles of CCR5 expression among primate speciesmay account for different sensitivity to IFN-I production andtherefore different patterns of regulation of IFN-I-stimulatedgenes during chronic HIV-1 or SIV infection ultimatelyaccounting for differences in disease susceptibility

43 Cytostatic and Proapoptotic Effects Type I IFN are widelyrecognized as the most potent natural mediators of antiviralactivity in humans [1 3] Because the life cycle of viruses isdirectly influenced by the intracellular environment efficientantiviral mechanisms have developed to interfere with basiccellular functions or in an even more resolute mannereliminate infected cells which represent the factories ofviral replication These goals are achieved by IFN-I via theupregulation of genes exerting cytostatic and proapoptoticactivities The broadly effective antiviral mechanisms includethe induction of molecular mechanisms interfering with pro-tein synthesis and cellular activity as well as the stimulationof ligandreceptor-dependent apoptotic pathways and stressresponses While exerting potent antiretroviral activity thesemechanisms clearly interferewith basic cellular functions andcarry a potentially destructive risk for the host hence theneed for tight regulation of both the kinetic of activation andthe restriction to specific anatomical locations

During HIV-1 infection the chronic induction of IFN-Iresponses may contribute to progressive immunodeficiency[10 146]

431 Ligand-Receptor Mediated Apoptosis Type I IFN posi-tively regulates the expression of tumor necrosis factor (TNF)family members capable of inducing apoptosis in cells whichexpress specific receptors Thus expression of FAS ligand(FasL) TNF-related apoptosis inducing ligand (TRAIL) andprogrammed death ligand (PDL) 1 are all directly regulatedby IFN-I signalling [21 146ndash148]

The contribution of the FasFasL system to CD4 T cellapoptosis during HIV-1 infection is well documented [149ndash151] and similar findings were reported for IFN-I-inducedTRAIL and its death receptor (DR)5 [55 65 121 152 153]TRAIL expression following HIV-1 exposure or infection hasbeen described in T cells monocytes and pDC [24 55 153154] and TRAIL expressing pDChave been shown to directlyinduce apoptosis of CD4 T cells in HIV-1 infected patientswith high viraemia [153] TRAIL mediated apoptosis in thesetting of HIV-1 stimulation in vitro was originally reportedto affect CD4 T cells but not CD8 T cells [55 65 152]Interestingly TRAIL mediated CD4 T cell apoptosis did notrequire productive infection and TRAIL expressing pDCwere reported to be unable to lyse HIV-1 infected CD4 Tcells [155] possibly favouring the depletion of uninfectedCD4 T helper cells in the face of CD4 T cell viral reservoirspreservation However Zhu et al later described TRAILdependent apoptosis in HIV-1 infected macrophages as aresult of the downregulation of a decoy receptor [156]Thus TRIAL induced apoptosis may contribute to regulating

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the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

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12 Scientifica

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[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

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[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

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[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

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[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

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[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

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[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

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[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 5

4 Effect of IFN-I on Target Cells

Type I IFN are the most potent natural mediators of antiviralactivity in humans The combination of proapoptotic andcytostatic activity as well as the direct induction of intracel-lular viral restriction factors contribute to generate a cellularenvironment which is unsuitable for viral replication [1 3 8283] The replication of HIV-1 is efficiently inhibited by IFN-I in vitro but the potential of IFN-I as antiretroviral agentsduring chronic HIV-1 infection in vivo is dubious [84ndash89]

IFN-I also contribute to the maturation of APC and exerta modulatory effect on different T cell subsets thereforeposing the foundations for promoting antigen-specific adap-tive immune responses and shaping them according to theinvading pathogen [1 6 7 53 82 90]

41 IFN-120572 Receptor Complex and Signalling The cellulareffects of IFN-I aremediated by the engagement of a commonreceptor complex the IFN-120572 receptor complex (IFNAR)which is expressed at different levels on the surface of virtuallyall human cells The IFNAR complex is a heterodimer of thetwo subunits IFNAR1 and IFNAR2 Human IFNAR1 com-prises an extracellular domain a transmembrane region andan intracellular domain of 100 amino acid residues Threedifferent forms of IFNAR2 have been described the fulllength receptor chain which includes a 250 residues cytoplas-mic portion an alternative form with a shorted intracellularportion (67 residues) [91 92] and a soluble form lackingthe transmembrane and cytoplasmic portions [91] HumanIFNAR2 binds all human IFN-I with higher affinity thanIFNAR1 but the affinity of the IFNAR heterodimer for mosthuman IFN-I is 10 fold higher than IFNAR2 alone [91 93 94]

The cytoplasmic domains of IFNAR1 and IFNAR2 areassociated with the tyrosine kinase (TYK)-2 and janus kin-ase (JAK)-1 respectively [91] Upon IFN-I binding to theIFNAR complex the tyrosine kinases are activated and orc-hestrate the signal transduction machinery [95] TYK-2and JAK-1 phosphorylate tyrosine residues on the IFNARand phosphorylated tyrosines act as docking sites for thesrc-homology-2 (SH2) domains of signal transducer andactivator of transcription (STAT) proteins which are thentargeted for phosphorylation [96 97] STAT1 STAT2 STAT3and STAT5 are expressed and activated by IFN-I in mostcell types whereas IFN-I-induced activation of STAT4 andSTAT6 is limited to lymphocytes [96 97]

STAT2 is recruited to the IFNAR1 cytoplasmic domainand is phosphorylated by TYK-2 serving as a lure for STAT1[98] which is also phosphorylated at tyrosine 701The STAT1-STAT2 heterodimer associates with the DNA binding proteininterferon regulatory factor 9 (IRF9) to form a signallingcomplex called IFN-stimulated gene factor-3 (ISGF3) TheISGF3 complex translocates to the nucleus where it promotesthe transcription of IFN-I-stimulated genes (ISG) by inter-acting with the IFN-stimulated response elements (ISRE)usually situated within 200 base pairs of the transcriptionstart site An additional phosphorilation of STAT1 at serine727 mediated by protein kinase C-120575 (PKC-120575) is essential forefficient transcriptional activity [1 98] In addition STAT1homodimers can bind to IFN-120574-activated site (GAS) in the

promoter region of IFN-I-stimulated genes [99 100] Thuswhile IFN-I can activate genes containing either ISRE or GASpromoter elements IFN-120574 is unable to induce the formationof ISGF3 and activate genes via ISRE [101] Signalling viaSTAT1-STAT2 is responsible for some of the most commonlyobserved effects of IFN-I during chronic HIV-1 infectionincluding the activation of proapoptotic and cytostatic genesviral restriction factors and immunomodulatory effects [102ndash104]

Type I IFN also triggers phosphorylation of STAT3[105] promoting its dimerization and migration to the nucl-eus STAT3 homodimers activate the transcription of genescontaining the enhancer sequence STAT3-binding element(SBE) Despite sharing high sequence similarity with STAT1STAT3 activation induces a gene expression profile distinctfrom that dependent on STAT1-STAT2 [106] including genesof the B cell lymphoma (BCL) family and the oncogeneMYC which promote proliferation and antagonize apoptosis[107 108] Furthermore STAT3 is responsible for the sup-pression of inflammatory responses via IL-10 which directlycounteracts STAT1 activity [109]

IFN-120573 also activates the signal transduction pathwaymediated by JAK1 and phosphoinositide 3-kinase (PI3K)leading to the expression of genes regulated by cyclic adeno-sine monophosphate (cAMP) via the nuclear translocation ofcAMP-responsive-element (CRE) binding protein (CREB)Similar to the STAT3-mediated pathway PI3K signalling canalso result in IL-10 production by DC [110] However thetwo pahways appear to be independent from each other Themammalian target of rapamycin (mTOR) is activated down-stream of the PI3K signalling cascade [111] Activation ofmTOR is independent of STAT signalling and does notmodify the gene expression profile but modulates mRNAtranslation by regulating the activation of p70 S6 kinase andthe phosphorylation of the ribosomal protein S6 [112 113]

The signalling pathway mediated by p38 mitogen-activ-ated protein kinases (p38-MAPK) and extracellular signal-regulated kinase (ERK) 1 or ERK2 is also activated by IFN-IThus genes which contain ISRE and GAS elements in theirpromoter region can be upregulated via a STAT-independentpathwaymediated by p38-MAPK [114ndash116] and the cytostaticand antiviral effects of IFN-I are dependent on intact p38-MAPK signalling machinery [117ndash120]

It is reasonable to expect that different IFN-I signaltransduction pathways are activated during HIV-1 infectionHowever the STAT1-STAT2 pathway is arguably the bestdescribed in the setting of IFN-I production during HIV-1 infection The activation of STAT proteins by HIV-1 wasdescribed in different experimental conditions involvingHIV-1-induced IFN-I production productive HIV-1 infec-tion of target cells or simple exposure to viral proteins Thusin vitro exposure of cell lines or primary leukocytes towhole HIV-1 virions was repeatedly shown to activate STAT-dependent pathways inCD4T cells and cells of themonocyticlineage [55 121 122] Interestingly Renga and colleaguesreported that exposure of monocytic cell lines to the HIV-1matrix protein p17 was sufficient to activate the JAK1STAT1axis and cause upregulation of STAT1 sensitive genes [123]suggesting that STAT1 activation during HIV-1 infectionmay

6 Scientifica

also occur independent of IFN-I production Simian immun-odeficiency virus (SIV) infection of nonhuman primates invivo resulted in upregulation of gene expression for STAT1STAT2 and IRF9 during the acute phase of infection whichwas protracted through the early chronic phase only indisease susceptible primate species not in disease resistantAfrican species [124 125] Although signalling via the ISGF3complex is regulated by post-transcriptional modification ofSTAT proteins not by modulation of STAT and IRF9 geneexpression the observed increases in the expression of thesemolecules in SIV-infectedmacaques [124 125] is indicative ofenhanced activity of the IFN-IISGF3 axis

The central role played by PI3K in multiple signal trans-duction pathways renders it difficult to distinguish its partici-pation in mediating the effects of IFN-I from other biochem-ical cellular and molecular events occurring during HIV-1infection The contribution of PI3K in neuroinflammationassociatedwithHIV-1 infection has been described [126ndash128]but the role of Pi3KmTOR in HIV-1 immunopathogenesisremains unclear

Activation of the p38-MAPK pathway during HIV-1 infe-ction has been described by several groups [129ndash139] How-ever studies on the p38-MAPKERK pathway have generallyfocused on the direct effect of HIV-1 gp120 singalling viaengagement of CD4 or the coreceptors CCR5 and CXCR4[129 136ndash139] rather than IFN-I production In particularactivation of p38-MAPKERK has been studied in referenceto its role in modulating cell activation and HIV-1 replication[129ndash135]

42 Expression Pattern of IFNAR Type I IFN are generallyconsidered to exert their biologic effect on virtually all humancells This broad and noncell specific activity reflects theprominent innate antiviral function of IFN-I which needs toreach any potential target of viral infection

However cell-specific differences in the responsivenessto IFN-I signalling have been observed in humans partic-ularly among immune effector cells Thus IFN-I inducingTLR9 agonists as well as HIV-1 efficiently upregulated theexpression of the IFN-I regulated gene PDL1 on primaryhuman monocytes and a subset of T lymphocytes identifiedby selective expression of the chemokine receptor CCR5 [21]Analysis of IFNAR2 expression in T lymphocytes revealedthat this subunit of IFNAR was almost exclusively restrictedto CCR5+ T cell subsets independent of whether CD4 orCD8 T cells were considered [21] A similar restriction ofIFN-I signalling to CCR5+ T cells was observed when HIV-1-induced upregulation of the T cell activationmarkers CD38and CD69 was analyzed in vitro [9 140]

In both humans and non-human primates CCR5 expres-sion is generally higher in memory and effector T cell subsets[141ndash144] and natural disease-resistant SIV host speciessuch as sooty mangabeys show reduced levels of CCR5+CD4 T cells compared to disease susceptible hosts such ashumans and Rhesus macaques [142 143] The role playedby CCR5 as coreceptor for HIV-1 and SIV Env proteinsproviding the critical mechanism for envelope-membranefusion and injection of the viral RNA into the cytoplasmprovided the basis for investigating how differences in CCR5

expression between different species translate into differenttransmission and disease progression phenotype [142 145]However little attention has been given to the possibility thatdifferent profiles of CCR5 expression among primate speciesmay account for different sensitivity to IFN-I production andtherefore different patterns of regulation of IFN-I-stimulatedgenes during chronic HIV-1 or SIV infection ultimatelyaccounting for differences in disease susceptibility

43 Cytostatic and Proapoptotic Effects Type I IFN are widelyrecognized as the most potent natural mediators of antiviralactivity in humans [1 3] Because the life cycle of viruses isdirectly influenced by the intracellular environment efficientantiviral mechanisms have developed to interfere with basiccellular functions or in an even more resolute mannereliminate infected cells which represent the factories ofviral replication These goals are achieved by IFN-I via theupregulation of genes exerting cytostatic and proapoptoticactivities The broadly effective antiviral mechanisms includethe induction of molecular mechanisms interfering with pro-tein synthesis and cellular activity as well as the stimulationof ligandreceptor-dependent apoptotic pathways and stressresponses While exerting potent antiretroviral activity thesemechanisms clearly interferewith basic cellular functions andcarry a potentially destructive risk for the host hence theneed for tight regulation of both the kinetic of activation andthe restriction to specific anatomical locations

During HIV-1 infection the chronic induction of IFN-Iresponses may contribute to progressive immunodeficiency[10 146]

431 Ligand-Receptor Mediated Apoptosis Type I IFN posi-tively regulates the expression of tumor necrosis factor (TNF)family members capable of inducing apoptosis in cells whichexpress specific receptors Thus expression of FAS ligand(FasL) TNF-related apoptosis inducing ligand (TRAIL) andprogrammed death ligand (PDL) 1 are all directly regulatedby IFN-I signalling [21 146ndash148]

The contribution of the FasFasL system to CD4 T cellapoptosis during HIV-1 infection is well documented [149ndash151] and similar findings were reported for IFN-I-inducedTRAIL and its death receptor (DR)5 [55 65 121 152 153]TRAIL expression following HIV-1 exposure or infection hasbeen described in T cells monocytes and pDC [24 55 153154] and TRAIL expressing pDChave been shown to directlyinduce apoptosis of CD4 T cells in HIV-1 infected patientswith high viraemia [153] TRAIL mediated apoptosis in thesetting of HIV-1 stimulation in vitro was originally reportedto affect CD4 T cells but not CD8 T cells [55 65 152]Interestingly TRAIL mediated CD4 T cell apoptosis did notrequire productive infection and TRAIL expressing pDCwere reported to be unable to lyse HIV-1 infected CD4 Tcells [155] possibly favouring the depletion of uninfectedCD4 T helper cells in the face of CD4 T cell viral reservoirspreservation However Zhu et al later described TRAILdependent apoptosis in HIV-1 infected macrophages as aresult of the downregulation of a decoy receptor [156]Thus TRIAL induced apoptosis may contribute to regulating

Scientifica 7

the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

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6 Scientifica

also occur independent of IFN-I production Simian immun-odeficiency virus (SIV) infection of nonhuman primates invivo resulted in upregulation of gene expression for STAT1STAT2 and IRF9 during the acute phase of infection whichwas protracted through the early chronic phase only indisease susceptible primate species not in disease resistantAfrican species [124 125] Although signalling via the ISGF3complex is regulated by post-transcriptional modification ofSTAT proteins not by modulation of STAT and IRF9 geneexpression the observed increases in the expression of thesemolecules in SIV-infectedmacaques [124 125] is indicative ofenhanced activity of the IFN-IISGF3 axis

The central role played by PI3K in multiple signal trans-duction pathways renders it difficult to distinguish its partici-pation in mediating the effects of IFN-I from other biochem-ical cellular and molecular events occurring during HIV-1infection The contribution of PI3K in neuroinflammationassociatedwithHIV-1 infection has been described [126ndash128]but the role of Pi3KmTOR in HIV-1 immunopathogenesisremains unclear

Activation of the p38-MAPK pathway during HIV-1 infe-ction has been described by several groups [129ndash139] How-ever studies on the p38-MAPKERK pathway have generallyfocused on the direct effect of HIV-1 gp120 singalling viaengagement of CD4 or the coreceptors CCR5 and CXCR4[129 136ndash139] rather than IFN-I production In particularactivation of p38-MAPKERK has been studied in referenceto its role in modulating cell activation and HIV-1 replication[129ndash135]

42 Expression Pattern of IFNAR Type I IFN are generallyconsidered to exert their biologic effect on virtually all humancells This broad and noncell specific activity reflects theprominent innate antiviral function of IFN-I which needs toreach any potential target of viral infection

However cell-specific differences in the responsivenessto IFN-I signalling have been observed in humans partic-ularly among immune effector cells Thus IFN-I inducingTLR9 agonists as well as HIV-1 efficiently upregulated theexpression of the IFN-I regulated gene PDL1 on primaryhuman monocytes and a subset of T lymphocytes identifiedby selective expression of the chemokine receptor CCR5 [21]Analysis of IFNAR2 expression in T lymphocytes revealedthat this subunit of IFNAR was almost exclusively restrictedto CCR5+ T cell subsets independent of whether CD4 orCD8 T cells were considered [21] A similar restriction ofIFN-I signalling to CCR5+ T cells was observed when HIV-1-induced upregulation of the T cell activationmarkers CD38and CD69 was analyzed in vitro [9 140]

In both humans and non-human primates CCR5 expres-sion is generally higher in memory and effector T cell subsets[141ndash144] and natural disease-resistant SIV host speciessuch as sooty mangabeys show reduced levels of CCR5+CD4 T cells compared to disease susceptible hosts such ashumans and Rhesus macaques [142 143] The role playedby CCR5 as coreceptor for HIV-1 and SIV Env proteinsproviding the critical mechanism for envelope-membranefusion and injection of the viral RNA into the cytoplasmprovided the basis for investigating how differences in CCR5

expression between different species translate into differenttransmission and disease progression phenotype [142 145]However little attention has been given to the possibility thatdifferent profiles of CCR5 expression among primate speciesmay account for different sensitivity to IFN-I production andtherefore different patterns of regulation of IFN-I-stimulatedgenes during chronic HIV-1 or SIV infection ultimatelyaccounting for differences in disease susceptibility

43 Cytostatic and Proapoptotic Effects Type I IFN are widelyrecognized as the most potent natural mediators of antiviralactivity in humans [1 3] Because the life cycle of viruses isdirectly influenced by the intracellular environment efficientantiviral mechanisms have developed to interfere with basiccellular functions or in an even more resolute mannereliminate infected cells which represent the factories ofviral replication These goals are achieved by IFN-I via theupregulation of genes exerting cytostatic and proapoptoticactivities The broadly effective antiviral mechanisms includethe induction of molecular mechanisms interfering with pro-tein synthesis and cellular activity as well as the stimulationof ligandreceptor-dependent apoptotic pathways and stressresponses While exerting potent antiretroviral activity thesemechanisms clearly interferewith basic cellular functions andcarry a potentially destructive risk for the host hence theneed for tight regulation of both the kinetic of activation andthe restriction to specific anatomical locations

During HIV-1 infection the chronic induction of IFN-Iresponses may contribute to progressive immunodeficiency[10 146]

431 Ligand-Receptor Mediated Apoptosis Type I IFN posi-tively regulates the expression of tumor necrosis factor (TNF)family members capable of inducing apoptosis in cells whichexpress specific receptors Thus expression of FAS ligand(FasL) TNF-related apoptosis inducing ligand (TRAIL) andprogrammed death ligand (PDL) 1 are all directly regulatedby IFN-I signalling [21 146ndash148]

The contribution of the FasFasL system to CD4 T cellapoptosis during HIV-1 infection is well documented [149ndash151] and similar findings were reported for IFN-I-inducedTRAIL and its death receptor (DR)5 [55 65 121 152 153]TRAIL expression following HIV-1 exposure or infection hasbeen described in T cells monocytes and pDC [24 55 153154] and TRAIL expressing pDChave been shown to directlyinduce apoptosis of CD4 T cells in HIV-1 infected patientswith high viraemia [153] TRAIL mediated apoptosis in thesetting of HIV-1 stimulation in vitro was originally reportedto affect CD4 T cells but not CD8 T cells [55 65 152]Interestingly TRAIL mediated CD4 T cell apoptosis did notrequire productive infection and TRAIL expressing pDCwere reported to be unable to lyse HIV-1 infected CD4 Tcells [155] possibly favouring the depletion of uninfectedCD4 T helper cells in the face of CD4 T cell viral reservoirspreservation However Zhu et al later described TRAILdependent apoptosis in HIV-1 infected macrophages as aresult of the downregulation of a decoy receptor [156]Thus TRIAL induced apoptosis may contribute to regulating

Scientifica 7

the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 7

the balance between clearance of HIV-1 infected cells anddepletion of CD4 T helper cells

Upregulation of PDL1 on circulating monocytes and Tcells during HIV-1 infection was originally described to cor-relate with active viral replication [157] The report of acausative link between IFN-I secretion and PDL1 expressionafter exposure to HIV-1 also indicated that CCR5 expressionon T cells is associated with sensitivity to IFN-I signallingdetermined by increased expression of IFNAR2 [21] PDL1engages its receptor PD1 on T lymphocytes to suppress prolif-eration and induce apoptosis [158] During HIV-1 infectionPD1 is highly expressed by exhausted dysfunctional HIV-1-specific T cells [159] and blockade of PD1-PDL1 interactionenhances HIV-1-specific T cell immunity and immune-med-iated control of viraemia in humanized mice and simianmodels of HIV-1 infection [160ndash164] Thus upregulation ofPDL1 via IFN-I may directly contribute to the impairment ofefficient antiviral T cell responses and to the perpetuation ofHIV-1 infection

432 P53-Mediated Apoptosis The existence of a functionalconnection between IFN-120572120573 and p53 we formally reportedby Takaoka and coworkers in 2003 [165] The relevancefor IFN-I-induced p53 activation for viral infections washighlighted by Vilcek who postulated that IFN-I-mediatedactivation of the STAT1-STAT2-IRF-9 complex (ISGF-3)during viral infection may promote p53 gene expression viatwo ISRE sites in the p53 gene promoter [83]

Doitsh and colleagues reported that the accumulation ofreverse transcription intermediates in CD4 T cells undergo-ing abortive HIV-1 infection results in apoptotic death [166]The apoptotic pathway induced by abortive infection wasassociated with the production of inflammatory cytokinesincluding IL-1120573 and IFN-120573 and involved activation of cas-pase-1 and caspase-3 [166] However the authors found noevidence of p53 involvement [166]

44 Viral Restriction Factors HIV-1 infection and replicationwithin infected cells can be inhibited at different steps of theviral life cycle by restriction factors regulated by IFN-I

441 Interferon Stimulated Gene 15 (ISG15) The 15 kDa pro-duct of the IFN-stimulated gene (ISG) 15 was originallyidentified as a ubiquitin homologue13 Similar to ubiquitinISG15 acts as a tag for cellular proteins via covalent bindingmediated by specific enzymes which are also positively regu-lated by IFN-I [167ndash170] However different from ubiquitinthe primary effect of tagging with ISG15 (often referred to asISGylation) does not appear to be proteasomal degradationFor example ISGylation favours the sustained production ofIFN-120573 in virus-infected cells by preventing the degradationof IRF3 [171] and enhances NF-120581B signalling by inhibiting theactivity of the protein phosphatase 1B (PPM1B) [172]

ISG15 has been shown to exert broad antiviral activity inbothmice and humans [167]The anti-HIV-1 activity of ISG15is mediated via inhibition of the ubiquitylation of the capsideprotein Gag and of the cellular protein encoded by the tumorsusceptibility gene (Tsg)101 [173 174] Ubiquitylation of Gag

and Tsg101 is required for the release of virions from infectedcells a processwhich is therefore inhibited by ISGylation [173174]

442 Myxovirus Resistance (Mx) GTPases Type I IFN ind-uce the expression of proteins involved in membrane rearr-angement leading to vesicle budding organogenesis andcytokinesis Some of these proteins may contribute to hostresistance to pathogens including the p47 and p65 guanylate-binding proteins (GBP) inducible GTPases and the myx-ovirus resistance (Mx) proteins [175] In particular the Mxproteins have been widely studied for their antiviral activityand their expression is strictly regulated by IFN-I [176]

Two Mx proteins have been identified in humans MxAand MxB MxA exerts inhibitory effect on a wide range ofviruses [167] MxB was recently described as a novel restri-ction factor for HIV-1 [177 178] The mechanism of HIV-1 inhibition is not fully elucidated but the viral cycle isblocked after viral entry and before proviral DNA integration[177 178] In addition binding to the capsid protein gag isrequired for the antiviral activity [177 178]

443 21015840-51015840-Oligoadenylate Synthetase (OAS) and RNaseLPathway The 21015840-51015840-oligoadenylate synthetase (OAS) prote-ins are IFN-I inducible enzymes which polymerize ATPinto oligomers of adenosine generated with noncanonical21015840-51015840 bonds [179 180] These 21015840-51015840 adenosine oligomersinduce activation of RNaseL which mediates degradationof RNA from invading viruses and suppression of cellularactivities [181] Degraded RNAmay also activate cytoplasmicRLR resulting in IFN-I production and amplification of theantiviral innate responses [182]

Specific anti-HIV-1 activity by the OAS-RNaseL axis hasbeen described in transfected cell lines [183] Although the invivo relevance of this antiviral system for HIV-1 inhibition isstill to be determined it is reasonable to speculate that thenon virus specific effect of RNaseL may partially affect HIV-1activity in target cells

444 Protein Kinase RNA-Activated (PKR) The protein kin-ase RNA-activated (PKR) is involved together with othermembers of the same family of protein kinases in the respo-nse to environmental stress Kinases in this family regulatethe rate of protein synthesis by phosphorylating the120572-subunitof the eukaryotic initiation factor (EIF) 2 which result in thesequestration of guanine-nucleotide exchange factor EIF2120573ultimately preventing the recycle of guanidin diphosphate(GDP) which is strictly necessary for protein synthesis [184]

PKR is constitutively expressed in all cell types in aninactive monomeric form and converts active homodimersfollowing autophosphorylation at key residues [185ndash188]Thepresence of two RNA-binding motifs in the N-terminalregion allows for direct activation of PKR by RNA [189 190]

PKR is a potent inhibitor of HIV-1 replication in humancell lines in vitro but exerts lower inhibitory activity inprimary cells [191ndash196] questioning the in vivo relevance ofPKR-mediated anti-HIV-1 activity HIV-1 messenger RNAcontain a target sequence at the 51015840 end which is recognized by

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

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12 Scientifica

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[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

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[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

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[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

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[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

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[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 Scientifica

the transactivating accessory protein Tat the trans-activatingresponse (TAR)RNAelement plays a critical role in activatingtranscription [197ndash199] PKR is sensitive to changes in thecytoplasmic concentration of TAR RNA sequences in thatlow amounts of TAR induce PKR activation whereas highTAR RNA concentrations exert an inhibitory effect on PKRactivity [200ndash202]

445 Tripartite Motif (TRIM) Proteins Members of thetripartite motif (TRIM) protein family participate in a broadrange of cellular functions including apoptosis and antiviralimmunity [203] Several TRIM proteins have been describedfor their ability to restrict retroviruses replication and manyare directly regulated by IFN-I in humans including TRIM5and TRIM22 [204ndash208]

TRIM5 is one of the best studied members of theTRIM family mainly because of its inhibitory activity againstHIV-1 TRIM5 blocks HIV-1 infection in the cytoplasmbefore reverse transcription is completed by recognizing andbinding the capsid protein lattice thus interfering with theuncoating and ultimately with reverse transcription [209]The antiretroviral effect is strictly dependent on TRIM5 E3ubiquitin ligase activity [210 211] and is associated withproteasome recruitment [212 213] TRIM5 itself is ubiqui-tinated and degraded when it exert inhibitory activity onrestriction-sensitive viruses [210 211 214 215] However it isstill unclear whether ubiquitination of HIV-1 capsid occursTRIM5 proteins from different nonhuman primate speciesshow varying potency of anti-HIV-1 activity The macaqueand owl monkey TRIM5 orthologues have been particularlywell studied due to the potent inhibition of HIV-1 infectionin cells from these species [216 217] which is associatedwith strong interaction with the HIV-1 virion core [218] Thehuman TRIM5 orthologue shows relatively low inhibitoryactivity on lab-adapted HIV-1 stains [205 219] but it is 10-fold more potent on certain primary HIV-1 isolates [220]

TRIM5 contributes to control viral transmission andreplication in SIV-infected non human primates [221ndash225]and differences in the rate of disease progression in HIV-1 infected patients correlate with TRIM5 expression andpolymorphisms [226ndash229] In addition Battivelli and col-leagues reported that HIV-1 variants selected by cytotoxicT lymphocyte pressure to escape T cell recognition may behighly sensitive to restriction by human TRIM5 [230]

In addition to its well-studied antiviral activity TRIM5has been the subject of studies characterizing its role as apattern recognition receptor (PRR) for the protein lattice ofretroviral capsid TRIM5 is required for dendritic cell acti-vation in response to lipopolysaccharide (LPS) [211] andthe signal transduction pathways involving AP-1 and NF-120581Bare activated by TRIM5 [211 231] Thus the interaction ofTRIM5 with the HIV-1 capsid lattice enhances the inductionof inflammatory cytokines [211]

Other TRIM proteins have been studied for their abilityto interfere with HIV-1 replication Human TRIM22 effi-ciently inhibits HIV-1 transcription and replication in pri-mary human monocyte derived macrophages [232 233]TRIM22 exert its antiviral activity after HIV-1 integra-tion and E3 ubiquitin ligase activity is not necessary for

TRIM22-mediated inhibition of HIV-1 replication [234]Depending on the cell type and subcellular localizationTRIM22 can inhibitHIV-1 transcription at nuclear level [234]or virion production in the cytoplasm [204]

446 Apolipoprotein B-Editing Catalytic Polypeptide 3(APOBEC3) Proteins The anti-HIV-1 activity of proteinsof the apolipoprotein B-editing catalytic polypeptide 3(APOBEC3) family was originally described in an effort tocharacterize the function of the HIV-1 accessory proteinvirion infectivity factor (Vif) which is required for HIV-1replication in primary CD4+ T cells and certain cell lines butnot in fully permissive lines Further studied demonstratedthat the human gene APOBEC3G is a potent inhibitor of thereplication of Vif-deficient HIV-1 [235]

The inhibition ofHIV-1 replication byAPOBEC3G (A3G)relies on its cytidine deaminase activity on both RNA andDNA causing the conversion of cytidine residues into uri-dines [236ndash238]This process results in both the alteration ofthe nucleotide sequence and the insertion of nonnatural bases(uredines) into the DNA strand [236ndash238] The enzymaticactivity of A3G is selective for the third cytidine in 51015840-CCCA-31015840 sequences [237 238] As a consequence of cytidine-to-uridine mutation the levels of HIV-1 cDNA in infectedcells are diminished It was initially thought that uredine-containing DNAwas degraded by host DNA repair enzymesbut inhibition of uracil DNA glycosidases is ineffective inrestoring HIV-1 cDNA levels [239] It has been suggested thatA3G activitymay interfere with the progression of the reversetranscriptase along the viral RNA template [240 241]

One important characteristic of A3G is the fact thatunless counteracted by Vif it is packaged into assemblingHIV-1 virions [242] Thus A3G-bearing virions can transferthe restriction factor to target cells [237 243ndash245]

The viral accessory protein Vif potently inhibits theantiviral activity of A3G by recruiting it for polyubiquiti-nation and proteasomal degradation thus preventing A3Gincorporation into newly formed virions [244 246ndash248]

Other human APOBEC proteins have been shown toexert anti-HIV-1 activity in vitro However only APOBEC3F(A3F) and APOBEC3H (A3H) haplotype II appear to havea significant effect in vivo [249] even though they appearto have lower potency and lower expression than A3GAccordingly A3G A3F andA3H are the only APOBEC3 pro-teins counteracted by Vif suggesting a dynamic evolutionaryinterplay between host restriction factors and viral escapemechanisms

447 Bone Marrow Stromal Cell Antigen 2 (BST2 Tetherin)The bone marrow stromal cell antigen 2 (BST2 or tetherin) istransmembrane protein with glycophosphatidylinositol lipidanchor at the C-terminal domain an extracellular 120572-helixdomain and a N-terminal transmembrane anchor [250]Similar to A3G tetherin was described as the IFN-I-inducedcellular restriction factor inhibited by a HIV-1 accessoryprotein namely Vpu [85 86 251 252] Thus in the absenceof Vpu HIV-1 virions budding from productively infectedcells are trapped or tethered (hence the name tetherin) on

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

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[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

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Research and TreatmentAIDS

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 9

the surface of infected cells [85 86 251 252] Tethered virionsare eventually internalization and accumulate in endosomes[251]

Tetherin exert antiviral activity on several families ofviruses [253ndash255] and it preserves antiviral activity in the faceof extensive mutations [256] suggesting that its function isnot strictly dependent on recognition of specific viral proteinsequences

HIV-1 evades the antiviral effect of tetherin thanks tothe accessory protein Vpu [86 252] Vpu directly binds teth-erin and causes a general decrease in tetherin expression onthe cell surface [252] Different mechanisms have been sugg-ested to account for Vpu-mediated counteracting of tetherinactivity including alterations of trafficking pathways [257258] and enhanced proteasomal degradation [259ndash261]

Other human and nonhuman primate lentiviruses havedeveloped mechanisms of evasion for tetherin-mediatedantiviral activity Thus most SIV do not encode Vpu andtetherin is antagonized by the Nef protein [262 263] Con-versely the Env protein of HIV-2 which also does not encodeVpu has evolved to interfere with tetherin and cause it to besequestered within intracellular compartments [264 265]

448 Sterile 120572 Motif (SAM) and Histidine-Aspartic (HD)Domain-Containing Protein 1 (SMAHD1) Studies on thefunction of another lentiviral accessory protein the viral pro-tein x (Vpx) brought to the discovery of the restriction factorsterile 120572 motif (SAM) and histidine-aspartic (HD) domain-containing protein 1 (SMAHD1)

Vpx is expressed by HIV-2 and related viruses (such asSIVsm) but not by HIV-1 [266] HIV-1 infection of humanmonocyte-derived dendritic cells is enhanced in presence ofexogenous Vpx or if HIV-1 is genetically modified to enco-de for Vpx [267 268] and HIV-2 reverse transcription inmonocyte-derived macrophages is strictly dependent on Vpx[269] A number of studies contributed to identify SAMHD1as the target of Vpx-driven ubiquitylation and subsequentproteosomal degradation Thus SAMHD1 ubiquitylation ismediated by the cullin-4A ubiquitin ligase (CUL4A)-DNAdamage-binding protein 1 (DDB1) complex (CUL4A-DDB1)which is assembled by Vpx via recruitment of the DDB1CUL4A associated factor 1 (DCAF1) [270ndash273]

SAMHD1 exerts phosphohydrolase activity and can deg-rade deoxyribonucleotides triphosphate (dNTP) to deoxynu-cleoside and inorganic triphosphate [274] Reverse transcrip-tion relies on the availability of dNTP and the anti-HIV-1 effect of SAMHD1 is mediated via its dNTPase activitywhich causes a reduction of the pool of intracellular dNTPto a level incompatible with viral replication [275] SAMHD1is exclusively localized in the nucleus [276ndash278] whereasreverse transcription occurs in large part in the cytoplasmsuggesting that dNTP hydrolysis in the nucleus has deleteri-ous repercussions on the cytoplasmic availability of dNTP

SAMHD1 is expressed at constitutively high levels bycells which are nonpermissive with regards to HIV-1 infec-tion such as monocytes and monocyte-derived DC [271]However HEK293T cells undifferentiated THP-1 cells andactivated CD4+ T cells are not refractory to HIV-1 infectiondespite expressing SAMHD1 [270 275] suggesting that the

antiviral activity of SAMHD1 may be biologically importantonly in differentiated or non-dividing cells such as DC andmacrophages The high rate of dNTP turnover in dividingcells overcoming the dNTPase activity may in part explainthe susceptibility to lentiviral infection despite SAMHD1expression SAMHD1 can be upregulated in human mono-cytes and monocyte-derived DC by either type I or type IIIFN [279 280]

45 Immunostimulatory and Modulatory Activites Type IIFN play a pivotal role in the transition from innate to ada-ptive immune responses by both stimulating maturation ofAPC and by directly modulating and shaping T cell function

451 Effect of IFN-I on APC Differentiation and MaturationIFN-I stimulates monocytes differentiation into DC in vitro[281ndash284] However the presence of IL-4 in the in vitro cul-ture ofmonocyte appears tomodify the effects of IFN-I likelydue to the ability of IL-4 to attenuate the expression of ISG[285] Thus the ultimate effect of IFN-I stimulation on thedifferentiation of monocytes into DC may depend on thecytokinemilieu in the surrounding environment and the tim-ing of exposure to different stimuli

Importantly IFN-I promotes the maturation of DC tofully competent APC by inducing upregulation of the costim-ulatorymolecules CD40 CD80 and CD86 and by enhancingthe expression of MHC class I and II [6 7 286 287] Thesechanges in DC phenotype correspond to increased ability ofIFN-I-stimulated DC to stimulate T cell proliferation in vitro[6 7 286 287]

Following IFN-I stimulation DC secrete IL-15 whichexert stimulatory effects on T cells and promotes DCmatura-tion [282 288] In addition IL-10 and the TNF family mem-bers B lymphocyte stimulator protein (BlyS) and APRIL arealso expressed by DC following IFN-I stimulation [289ndash291]When expressed in combination with IL-10 or transforminggrowth factor (TGF)120573 APRIL can induce T cell independentimmunoglobulin class switching [291] IL-10 is a potent anti-inflammatory mediator its production in response to IFN-I highlights the dichotomous role that IFN-I may play inbalancing immune activation and immune suppression [289]Accordingly the effect of IFN-120572120573 on IL-12 production can beeither stimulatory or inhibitory [292ndash294] The maturationstage of DC and the dose of IFN-I to which they are exposedmay all affect IL-12 production as well as the interaction ofIFN-I with other stimuli [295 296] Changes in the secretionof IL-12 may then affect the quality of the DC-activated Tcell response bymodulating the induction of IFN-120574-secretingcells as well as the production of other cytokines such as IL-4IL-5 IL-10 and IL-13 [289]

The secretion of chemokine is also modulated by IFN-IMonocyte-derived immatureDC secrete the CXCR3-bindingchemokines CXCL9 CXCL11 and CXCL10 in response toIFN-I stimulation [287] CXCR3 is expressed by activated Tand B cells [297] which may be recruited to sites of inflam-mation In addition IFN-I induces DC-mediated secretionof CXCL19 (MIP-3120573) which recruits naive T cells and maytherefore contribute to initiating adaptive T cell responses[298]

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 Scientifica

452Modulation of T Cell Response Thedirect effect of IFN-I on proapoptotic and immunoregulatory ligands such asFasL TRAIL and PDL1 has been discussed in Section 43

The influence that IFN-I exert on APC maturation andcytokine production underscore the key role played in thedifferentiation of both CD4 and CD8 T cells Thus the enha-ncement of IL-12 production observed whenDC arematuredin presence of IFN-I induces STAT4 activation and sub-sequent T-bet expression in CD4 T cells which drive thedifferentiation into IFN-120574-producing T helper (Th)1 cells[299] In addition IFN-I directly act on human T cells toinduce STAT4 activation [300 301] which is however notsufficient on its own to drive Th1 commitment in vitro [302303] Conversely in presence of other cytokines such as IL-18and IL-21 IFN-I efficiently promotes Th1 cell differentiationand effector functions [304ndash306]

In parallel to the positive effects on Th1 differentiationIFN-I may inhibit or reverse CD4 T cell differentiation intoother Th types Thus Th2 responses are negatively regu-lated by IFN-I in human cells via the suppression of theTh2-driving transcription GATA-binding protein 3 (GATA3)[304] Furthermore suppression of Th17 differentiation byIFN-I has been described in both murine and human cells[307 308]

IFN-I may also contribute to negatively modulate T cellresponse by regulating the function of CD4 regulatory Tcells (Treg) which play a critical role in the maintenance ofimmunological tolerance and homeostasis Studies conduc-ted in patients with relapsing-remitting multiple sclerosishave highlighted how administration of IFN-120573 treatmentenhanced both the frequency and suppressive function of119879Reg cells [130]

The primary response of CD8 T cell against viral infec-tion epitomized by proliferation and clonal expansion canbe enhanced in presence of IFN-I which is also critical inallowing the generation of memory CD8 T cells [309ndash311]However secondary CD8 and CD4 T cell responses aga-inst viral antigens including HIV-1 may be inhibited inpresence of high levels of IFN-I [9 21] Thus the effect ofIFN-I on T cell responses may largely depend on the stim-ulation condition and the cell types affected in that IFN-Imay favour costimulatory signals during primary antigen-specific responses by naive T cells but suppress secondarymemory responses against recall antigens via the inductionof cytostatic and proapoptotic mechanisms

5 Conclusion and New Perspectives

Type I IFN play a central role in the coordination of amultitude of immune effector and regulatory mechanismsThe ultimate effect of IFN-I on the overall economy ofan effective antiviral immune response may depend on themechanism of induction the cellular source and the timingof production

Plasmacytoid DC may respond rapidly to viral exposureThe ability of pDC to secrete IFN-I in response TLR79signalling indicates that these cells do not require the viralgenome to enter the cytoplasm meaning that they produceIFN-I independent of whether they are productively infected

(Section 21) Combining IFN-I productionwith the potentialto mature into APC pDC may be the ideal candidate to pro-mote efficient antiviral primary T cell responses by favouringCD4 T cell differentiation into Th1 cells and favouring theactivation and clonal expansion of virus-specific naive CD8T cells (Sections 31 and 45)The local production of IFN-Iat the site of infection by pDC also favours the induction ofantiviral mechanisms whichmay limit the spread of infection(Section 44)

When productive infection of some tissue target cells isestablished IFN-I production may be sustained by infectedcells which do not normally exert immune function but canreact to viral genomes in the cytoplasm via specific sensors(Sections 22 and 23) Although limited in terms of amountof IFN-I produced on a per cell basis this second pDC-independent wave of IFN-I production may be more focusedand circumscribed to the foci of potential viral replicationand efficiently inhibit virus spread to other cells withoutinterfering with adaptive immune responses

During HIV-1 infection both the early pDC-mediatedand the late pDC-independent IFN-I responses may bedysfunctional and cause severe damage to the developmentand maintenance of adaptive anti-HIV-1 responsesThus theorganization of the HIV-1 envelope into a functional lipid raftmay favour an overwhelming induction of pDC-mediatedpersistent IFN-I responses over antigen-presenting function(Section 31) which may prevent the efficient promotion ofprimary CD4 Th1 and CD8 T cell responses Subsequentlythe tropism of HIV-1 for immune cells including DCand monocytemacrophages may result in the prolongedproduction of IFN-I in lymphoid tissues by HIV-1-infectedprofessional APC which may compromise the induction ofsecondary HIV-1-specific responses and contribute to theperpetuation of infection and disease progression

References

[1] J Bekisz H Schmeisser J Hernandez N D Goldman and KC Zoon ldquoHuman interferons alpha beta and omegardquo GrowthFactors vol 22 no 4 pp 243ndash251 2004

[2] S J Neil ldquoThe antiviral activities of tetherinrdquo Current Topics inMicrobiology and Immunology vol 371 pp 67ndash104 2013

[3] C E Samuel ldquoAntiviral actions of interferonsrdquo Clinical Micro-biology Reviews vol 14 no 4 pp 778ndash809 2001

[4] C Scagnolari and G Antonelli ldquoAntiviral activity of theinterferon alpha family biological and pharmacological aspectsof the treatment of chronic hepatitis crdquo Expert Opinion onBiological Therapy vol 13 pp 693ndash711 2013

[5] U Kalinke and M Prinz ldquoEndogenous or therapeuticallyinduced type I interferon responses differentially modulateTh1Th17-mediated autoimmunity in the CNSrdquo Immunologyand Cell Biology vol 90 pp 505ndash509 2012

[6] D F Tough ldquoModulation of t-cell function by type i interferonrdquoImmunology amp Cell Biology vol 90 pp 492ndash497 2012

[7] J M Gonzalez-Navajas J Lee M David and E Raz ldquoImm-unomodulatory functions of type i interferonsrdquoNature ReviewsImmunology vol 12 no 2 pp 125ndash135 2012

[8] L Frasca and R Lande ldquoOverlapping additive and counterreg-ulatory effects of type II and i interferons on myeloid dendritic

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

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[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

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[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

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[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

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[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

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[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

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[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

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[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

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BioMed Research International

OncologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 11

cell functionsrdquo The Scientific World Journal vol 11 pp 2071ndash2090 2011

[9] A Boasso C M Royle S Doumazos et al ldquoOveractivation ofplasmacytoid dendritic cells inhibits antiviral T-cell responsesa model for HIV immunopathogenesisrdquo Blood vol 118 no 19pp 5152ndash5162 2011

[10] A Boasso and G M Shearer ldquoChronic innate immune activa-tion as a cause of HIV-1 immunopathogenesisrdquo Clinical Immu-nology vol 126 no 3 pp 235ndash242 2008

[11] A Benlahrech and S Patterson ldquoHIV-1 infection and inductionof interferon alpha in plasmacytoid dendritic cellsrdquo CurrentOpinion in HIV and AIDS vol 6 no 5 pp 373ndash378 2011

[12] A-S Beignon K McKenna M Skoberne et al ldquoEndocytosisof HIV-1 activates plasmacytoid dendritic cells via Toll-likereceptor-viral RNA interactionsrdquo Journal of Clinical Investiga-tion vol 115 no 11 pp 3265ndash3275 2005

[13] M Kader A P Smith C Guiducci et al ldquoBlocking tlr7- andtlr9-mediated ifn-alpha production by plasmacytoid dendriticcells does not diminish immune activation in early siv infec-tionrdquo PLOS Pathogens vol 9 Article ID e1003530 2013

[14] A Szabo and E Rajnavolgyi ldquoCollaboration of toll-like and rig-i-like receptors in human dendritic cells triggering antiviralinnate immune responsesrdquo American Journal of Clinical andExperimental Immunology vol 2 pp 195ndash207 2013

[15] E M Creagh and L A J OrsquoNeill ldquoTLRs NLRs and RLRs a tri-nity of pathogen sensors that co-operate in innate immunityrdquoTrends in Immunology vol 27 no 8 pp 352ndash357 2006

[16] O Takeuchi and S Akira ldquoRecognition of viruses by innateimmunityrdquo Immunological Reviews vol 220 no 1 pp 214ndash2242007

[17] H J Ramos and M Gale Jr ldquoRIG-I like receptors and theirsignaling crosstalk in the regulation of antiviral immunityrdquoCurrent Opinion in Virology vol 1 no 3 pp 167ndash176 2011

[18] D Goubau S Deddouche and E S C Reis ldquoCytosolic sensingof virusesrdquo Immunity vol 38 pp 855ndash869 2013

[19] S R Paludan andAG Bowie ldquoImmune sensing ofDNArdquo Imm-unity vol 38 pp 870ndash880 2013

[20] T Kawai and S Akira ldquoInnate immune recognition of viral infe-ctionrdquo Nature Immunology vol 7 no 2 pp 131ndash137 2006

[21] A Boasso AWHardy A L Landay et al ldquoPDL-1 upregulationonmonocytes andT cells byHIVvia type I interferon restrictedexpression of type I interferon receptor by CCR5-expressingleukocytesrdquo Clinical Immunology vol 129 no 1 pp 132ndash1442008

[22] J-F Fonteneau M Larsson A-S Beignon et al ldquoHuman imm-unodeficiency virus type 1 activates plasmacytoid dendriticcells and concomitantly induces the bystander maturation ofmyeloid dendritic cellsrdquo Journal of Virology vol 78 no 10 pp5223ndash5232 2004

[23] M OrsquoBrien O Manches R L Sabado et al ldquoSpatiotemporaltrafficking of HIV in human plasmacytoid dendritic cells def-ines a persistently IFN-120572-producing and partially maturedphenotyperdquo Journal of Clinical Investigation vol 121 no 3 pp1088ndash1101 2011

[24] A W Hardy D R Graham G M Shearer and J-P HerbeuvalldquoHIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors byToll-like receptor 7-induced IFN-120572rdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no44 pp 17453ndash17458 2007

[25] D Harrich and B Hooker ldquoMechanistic aspects of HIV-1 reve-rse transcription initiationrdquoReviews inMedical Virology vol 12no 1 pp 31ndash45 2002

[26] L Kleiman RHalwani andH Javanbakht ldquoThe selective pack-aging and annealing of primer tRNALys3 in HIV-1rdquo CurrentHIV Research vol 2 no 2 pp 163ndash175 2004

[27] N Arhel ldquoRevisiting HIV-1 uncoatingrdquo Retrovirology vol 7article 96 2010

[28] M Gilliet W Cao and Y-J Liu ldquoPlasmacytoid dendritic cellssensing nucleic acids in viral infection and autoimmune dise-asesrdquo Nature Reviews Immunology vol 8 no 8 pp 594ndash6062008

[29] S Akira and K Takeda ldquoToll-like receptor signallingrdquo NatureReviews Immunology vol 4 no 7 pp 499ndash511 2004

[30] L A J OrsquoNeill ldquoHow Toll-like receptors signal what we knowand what we donrsquot knowrdquo Current Opinion in Immunology vol18 no 1 pp 3ndash9 2006

[31] C Guiducci C Ghirelli M-A Marloie-Provost et al ldquoPI3K iscritical for the nuclear translocation of IRF-7 and type I IFNproduction by human plasmacytoid predendritic cells in res-ponse to TLR activationrdquo Journal of ExperimentalMedicine vol205 no 2 pp 315ndash322 2008

[32] Y Osawa S Iho R Takauji et al ldquoCollaborative action of NF-120581B and p38MAPK is involved inCpGDNA-induced IFN-120572 andchemokine production in human plasmacytoid dendritic cellsrdquoJournal of Immunology vol 177 no 7 pp 4841ndash4852 2006

[33] B Baban P R Chandler B A Johnson III et al ldquoPhysiologiccontrol of IDO competence in splenic dendritic cellsrdquo Journalof Immunology vol 187 no 5 pp 2329ndash2335 2011

[34] A K Manlapat D J Kahler P R Chandler D H Munn andA LMellor ldquoCell-autonomous control of interferon type I exp-ression by indoleamine 2 3-dioxygenase in regulatory CD19+dendritic cellsrdquo European Journal of Immunology vol 37 no 4pp 1064ndash1071 2007

[35] A Boasso J-P Herbeuval A W Hardy et al ldquoHIV inhibitsCD4+ T-cell proliferation by inducing indoleamine 23-diox-ygenase in plasmacytoid dendritic cellsrdquo Blood vol 109 no 8pp 3351ndash3359 2007

[36] B Tavano R P Galao D R Graham et al ldquoIg-like transcript7 but not bone marrow stromal cell antigen 2 (also known ashm1 24 tetherin or cd317) modulates plasmacytoid dendriticcell function in primary human blood leukocytesrdquoThe Journalof Immunology vol 190 no 6 pp 2622ndash2630 2013

[37] P Puccetti and U Grohmann ldquoIDO and regulatory T cells arole for reverse signalling and non-canonical NF-120581B activationrdquoNature Reviews Immunology vol 7 no 10 pp 817ndash823 2007

[38] K Hoshino T Sugiyama M Matsumoto et al ldquoI120581B kinase-120572 is critical for interferon-120572 production induced by Toll-likereceptors 7 and 9rdquoNature vol 440 no 7086 pp 949ndash953 2006

[39] C Guiducci G Ott J H Chan et al ldquoProperties regulating thenature of the plasmacytoid dendritic cell response to Toll-likereceptor 9 activationrdquo Journal of Experimental Medicine vol203 no 8 pp 1999ndash2008 2006

[40] O Takeuchi and S Akira ldquoPattern recognition receptors andinflammationrdquo Cell vol 140 no 6 pp 805ndash820 2010

[41] R K Berg J Melchjorsen J Rintahaka et al ldquoGenomic HIVRNA induces innate immune responses through RIG-I-depe-ndent sensing of secondary-structured RNArdquo PLoS ONE vol 7no 1 Article ID e29291 2012

[42] Y Okabe K Kawane S Akira T Taniguchi and S NagataldquoToll-like receptor-independent gene induction program acti-vated by mammalian DNA escaped from apoptotic DNA

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

12 Scientifica

degradationrdquo Journal of Experimental Medicine vol 202 no 10pp 1333ndash1339 2005

[43] V Hornung A Ablasser M Charrel-Dennis et al ldquoAIM2 reco-gnizes cytosolic dsDNA and forms a caspase-1-activating infla-mmasome with ASCrdquo Nature vol 458 no 7237 pp 514ndash5182009

[44] K J Ishii C Coban H Kato et al ldquoA toll-like receptor-inde-pendent antiviral response induced by double-stranded b-formDNArdquo Nature Immunology vol 7 pp 40ndash48 2006

[45] S Sharma R B DeOliveira P Kalantari et al ldquoInnate immunerecognition of an AT-rich stem-loop DNA motif in the plas-modium falciparum genomerdquo Immunity vol 35 no 2 pp 194ndash207 2011

[46] D L Burdette and R E Vance ldquoSting and the innate immuneresponse to nucleic acids in the cytosolrdquo Nature Immunologyvol 14 pp 19ndash26 2013

[47] H Ishikawa and G N Barber ldquoThe STING pathway and regu-lation of innate immune signaling in response to DNA path-ogensrdquo Cellular and Molecular Life Sciences vol 68 no 7 pp1157ndash1165 2011

[48] H Ishikawa Z Ma and G N Barber ldquoSTING regulates intra-cellular DNA-mediated type i interferon-dependent innateimmunityrdquo Nature vol 461 no 7265 pp 788ndash792 2009

[49] H Ishikawa and G N Barber ldquoSTING is an endoplasmic retic-ulum adaptor that facilitates innate immune signallingrdquoNaturevol 455 no 7213 pp 674ndash678 2008

[50] Y Tanaka and Z J Chen ldquoSTING specifies IRF3 phosphoryla-tion by TBK1 in the cytosolic DNA signaling pathwayrdquo ScienceSignaling vol 5 no 214 article ra20 2012

[51] D Gao J Wu Y T Wu et al ldquoCyclic gmp-amp synthase is aninnate immune sensor of hiv and other retrovirusesrdquo Sciencevol 341 pp 903ndash906 2013

[52] M R Jakobsen R O Bak A Andersen et al ldquoIfi16 senses DNAforms of the lentiviral replication cycle and controls hiv-1 repl-icationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 110 no 48 pp E4571ndashE4580 2013

[53] M Colonna G Trinchieri and Y-J Liu ldquoPlasmacytoid den-dritic cells in immunityrdquo Nature Immunology vol 5 no 12 pp1219ndash1226 2004

[54] A G Jegalian F Facchetti and E S Jaffe ldquoPlasmacytoid den-dritic cells physiologic roles and pathologic statesrdquo Advances inAnatomic Pathology vol 16 no 6 pp 392ndash404 2009

[55] J-P Herbeuval A W Hardy A Boasso et al ldquoRegulationof TNF-related apoptosis-inducing ligand on primary CD4+T cells by HIV-1 role of type I IFN-producing plasmacytoiddendritic cellsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 102 no 39 pp 13974ndash139792005

[56] E Chertova O Chertov L V Coren et al ldquoProteomicand biochemical analysis of purified human immunodeficie-ncy virus type 1 produced from infected monocyte-derivedmacrophagesrdquo Journal of Virology vol 80 no 18 pp 9039ndash90522006

[57] Z Liao J W Roos and J E K Hildreth ldquoIncreased infectivityof HIV type 1 particles bound to cell surface and solid-phaseICAM-1 and VCAM-1 through acquired adhesion moleculesLFA-1 andVLA-4rdquoAIDSResearch andHumanRetroviruses vol16 no 4 pp 355ndash366 2000

[58] J Arthos C Cicala E Martinelli et al ldquoHIV-1 envelope proteinbinds to and signals through integrin 12057241205737 the gut mucosalhoming receptor for peripheral T cellsrdquo Nature Immunologyvol 9 no 3 pp 301ndash309 2008

[59] M E Linde D R Colquhoun C U Mohien et al ldquoThe con-served set of host proteins incorporated into hiv-1 virionssuggests a common egress pathway in multiple cell typesrdquo Jou-rnal of Proteome Research vol 12 pp 2045ndash2054 2013

[60] D R M Graham E Chertova J M Hilburn L O Arthur andJ E K Hildreth ldquoCholesterol depletion of human immunodefi-ciency virus type 1 and simian immunodeficiency virus with 120573-cyclodextrin inactivates and permeabilizes the virions evidencefor virion-associated lipid raftsrdquo Journal of Virology vol 77 no15 pp 8237ndash8248 2003

[61] Z Liao D R Graham and J E K Hildreth ldquoLipid rafts andHIV pathogenesis virion-associated cholesterol is required forfusion and infection of susceptible cellsrdquo AIDS Research andHuman Retroviruses vol 19 no 8 pp 675ndash687 2003

[62] Q Li J D Estes P M Schlievert et al ldquoGlycerol monolaurateprevents mucosal SIV transmissionrdquo Nature vol 458 no 7241pp 1034ndash1038 2009

[63] R Lubong Sabado M OrsquoBrien A Subedi et al ldquoEvidenceof dysregulation of dendritic cells in primary HIV infectionrdquoBlood vol 116 no 19 pp 3839ndash3852 2010

[64] J-P Herbeuval J Nilsson A Boasso et al ldquoHAART reducesdeath ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infectedmacaquesrdquo AIDS vol 23 no 1 pp 35ndash40 2009

[65] J-P Herbeuval J Nilsson A Boasso et al ldquoDifferential expres-sion of IFN-120572 and TRAILDR5 in lymphoid tissue of progressorversus nonprogressor HIV-1-infected patientsrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 103 no 18 pp 7000ndash7005 2006

[66] M Nascimbeni L Perie L Chorro et al ldquoPlasmacytoid den-dritic cells accumulate in spleens fromchronicallyHIV-infectedpatients but barely participate in interferon-120572 expressionrdquoBlood vol 113 no 24 pp 6112ndash6119 2009

[67] A Benlahrech A Yasmin S J Westrop et al ldquoDysregulatedimmunophenotypic attributes of plasmacytoid but not myeloiddendritic cells in hiv-1 infected individuals in the absence ofhighly active anti-retroviral therapyrdquo Clinical amp ExperimentalImmunology vol 170 pp 212ndash221 2012

[68] O Levy E E Suter R L Miller and M R Wessels ldquoUniqueefficacy of Toll-like receptor 8 agonists in activating humanneonatal antigen-presenting cellsrdquo Blood vol 108 no 4 pp1284ndash1290 2006

[69] V J Philbin and O Levy ldquoImmunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes basic mech-anisms and translational opportunitiesrdquo Biochemical SocietyTransactions vol 35 no 6 pp 1485ndash1491 2007

[70] V Piguet and R M Steinman ldquoThe interaction of HIV withdendritic cells outcomes and pathwaysrdquo Trends in Immunologyvol 28 no 11 pp 503ndash510 2007

[71] K Lore and M Larsson ldquoThe role of dendritic cells in thepathogenesis of HIV-1 infectionrdquo APMIS vol 111 no 7-8 pp776ndash788 2003

[72] J J Mattapallil D C Douek B Hill Y Nishimura M MartinandM Roederer ldquoMassive infection and loss of memory CD4+T cells in multiple tissues during acute SIV infectionrdquo Naturevol 434 no 7037 pp 1093ndash1097 2005

[73] J M Brenchley T W Schacker L E Ruff et al ldquoCD4+ T celldepletion during all stages ofHIVdisease occurs predominantlyin the gastrointestinal tractrdquo Journal of Experimental Medicinevol 200 no 6 pp 749ndash759 2004

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 13

[74] L J Picker ldquoImmunopathogenesis of acute AIDS virus infec-tionrdquo Current Opinion in Immunology vol 18 no 4 pp 399ndash405 2006

[75] L Tarassishin A Bauman H S Suh and S C Lee ldquoAnti-viral and anti-inflammatory mechanisms of the innate immunetranscription factor interferon regulatory factor 3 relevance tohuman cns diseasesrdquo Journal of NeuroImmune Pharmacologyvol 8 pp 132ndash144 2013

[76] L Pulliam H Rempel B Sun L Abadjian C Calosing and DJ Meyerhoff ldquoA peripheral monocyte interferon phenotype inHIV infection correlates with a decrease in magnetic resonancespectroscopy metabolite concentrationsrdquo AIDS vol 25 no 14pp 1721ndash1726 2011

[77] J Xu and T Ikezu ldquoThe comorbidity of HIV-associated neuroc-ognitive disorders and alzheimerrsquos disease a foreseeable med-ical challenge in post-HAART erardquo Journal of NeuroimmunePharmacology vol 4 no 2 pp 200ndash212 2009

[78] KGrovit-Ferbas andM EHarris-White ldquoThinking aboutHIVthe intersection of virus neuroinflammation and cognitivedysfunctionrdquo Immunologic Research vol 48 no 1-3 pp 40ndash582010

[79] S Gartner and Y Liu ldquoInsights into the role of immune activa-tion in HIV neuropathogenesisrdquo Journal of NeuroVirology vol8 no 2 pp 69ndash75 2002

[80] S Tattermusch and C R Bangham ldquoHtlv-1 infection whatdetermines the risk of inflammatory diseaserdquo Trends in Micro-biology vol 20 pp 494ndash500 2012

[81] S Tattermusch J A Skinner D Chaussabel et al ldquoSystems biol-ogy approaches reveal a specific interferon-inducible signaturein HTLV-1 associated myelopathyrdquo PLoS Pathogens vol 8 no 1Article ID e1002480 2012

[82] G N Barber ldquoHost defense viruses and apoptosisrdquo Cell Deathand Differentiation vol 8 no 2 pp 113ndash126 2001

[83] J Vilcek ldquoBoosting p53 with interferon and virusesrdquo NatureImmunology vol 4 no 9 pp 825ndash826 2003

[84] Y-L Chiu and W C Greene ldquoThe APOBEC3 cytidine deami-nases an innate defensive network opposing exogenous retro-viruses and endogenous retroelementsrdquo Annual Review ofImmunology vol 26 pp 317ndash353 2008

[85] S J D Neil V Sandrin W I Sundquist and P D Bieniasz ldquoAninterferon-120572-induced tethering mechanism inhibits HIV-1 andebola virus particle release but is counteracted by the HIV-1 vpuproteinrdquo Cell Host and Microbe vol 2 no 3 pp 193ndash203 2007

[86] S J D Neil T Zang and P D Bieniasz ldquoTetherin inhibitsretrovirus release and is antagonized byHIV-1 vpurdquoNature vol451 no 7177 pp 425ndash430 2008

[87] G Peng J L Ke W Jin T Greenwell-Wild and S M WahlldquoInduction of APOBEC3 family proteins a defensive maneuverunderlying interferon-induced anti-HIV-1 activityrdquo Journal ofExperimental Medicine vol 203 no 1 pp 41ndash46 2006

[88] P M Pitha ldquoMultiple effects of interferon on the replication ofhuman immunodeficiency virus type 1rdquo Antiviral Research vol24 no 2-3 pp 205ndash219 1994

[89] K M Rose M Marin S L Kozak and D Kabat ldquoTranscrip-tional regulation of APOBEC3G a cytidine deaminase thathypermutates human immunodeficiency virusrdquo The Journal ofBiological Chemistry vol 279 no 40 pp 41744ndash41749 2004

[90] R M Steinman and H Hemmi ldquoDendritic cells translatinginnate to adaptive immunityrdquo Current Topics in Microbiologyand Immunology vol 311 pp 17ndash58 2006

[91] D Novick B Cohen and M Rubinstein ldquoThe human inter-feron 120572120573 receptor characterization and molecular cloningrdquoCell vol 77 no 3 pp 391ndash400 1994

[92] L M Pfeffer L Basu S R Pfeffer et al ldquoThe short form of theinterferon 120572120573 receptor chain 2 acts as a dominant negative fortype I interferon actionrdquoTheJournal of Biological Chemistry vol272 no 17 pp 11002ndash11005 1997

[93] E C Cutrone and J A Langer ldquoContributions of cloned typeI interferon receptor subunits to differential ligand bindingrdquoFEBS Letters vol 404 no 2-3 pp 197ndash202 1997

[94] D Russell-Harde H Pu M Betts R N Harkins H D Perezand E Croze ldquoReconstitution of a high affinity binding site fortype I interferonsrdquoThe Journal of Biological Chemistry vol 270no 44 pp 26033ndash26036 1995

[95] G C Sen ldquoViruses and interferonsrdquo Annual Review of Microbi-ology vol 55 pp 255ndash281 2001

[96] S Matikainen T Sareneva T Ronni A Lehtonen P J Koski-nen and I Julkunen ldquoInterferon-120572 activatesmultiple STATpro-teins and upregulates proliferation-associated IL-2R120572 c-mycand pim-1 genes in human T cellsrdquo Blood vol 93 no 6 pp1980ndash1991 1999

[97] E Fasler-Kan A Pansky M Wiederkehr M Battegay and MH Heim ldquoInterferon-120572 activates signal transducers and acti-vators of transcription 5 and 6 in Daudi cellsrdquo European Journalof Biochemistry vol 254 no 3 pp 514ndash519 1998

[98] S Goodbourn L Didcock and R E Randall ldquoInterferons cellsignalling immune modulation antiviral responses and viruscountermeasuresrdquo Journal of General Virology vol 81 no 10pp 2341ndash2364 2000

[99] D S Aaronson and C M Horvath ldquoA road map for those whodonrsquot know JAK-STATrdquo Science vol 296 no 5573 pp 1653ndash1655 2002

[100] L C Platanias and E N Fish ldquoSignaling pathways activated byinterferonsrdquo Experimental Hematology vol 27 no 11 pp 1583ndash1592 1999

[101] L C Platanias ldquoMechanisms of type-I- and type-II-interferon-mediated signallingrdquo Nature Reviews Immunology vol 5 no 5pp 375ndash386 2005

[102] M Brucet L Marques C Sebastian J Lloberas and A CeladaldquoRegulation ofmurine Tap1 and Lmp2 genes inmacrophages byinterferon gamma is mediated by STAT1 and IRF-1rdquo Genes andImmunity vol 5 no 1 pp 26ndash35 2004

[103] M L Dustin K H Singer D T Tuck and T A Springer ldquoAdh-esion of T lymphoblasts to epidermal keratinocytes is regulatedby interferon 120574 and is mediated by intercellular adhesionmolecule 1 (ICAM-1)rdquo Journal of Experimental Medicine vol167 no 4 pp 1323ndash1340 1988

[104] A Yoshimura ldquoSignal transduction of inflammatory cytokinesand tumor developmentrdquoCancer Science vol 97 no 6 pp 439ndash447 2006

[105] T Sato C Selleri N S Young and J PMaciejewski ldquoInhibitionof interferon regulatory factor-1 expression results in predom-inance of cell growth stimulatory effects of interferon-120574 due tophosphorylation of Stat1 and Stat3rdquo Blood vol 90 no 12 pp4749ndash4758 1997

[106] S J Baker S G Rane and E P Reddy ldquoHematopoietic cytokinereceptor signalingrdquo Oncogene vol 26 no 47 pp 6724ndash67372007

[107] J Azare K Leslie H Al-Ahmadie et al ldquoConstitutively acti-vated stat3 induces tumorigenesis and enhances cell motilityof prostate epithelial cells through integrin 1205736rdquo Molecular andCellular Biology vol 27 no 12 pp 4444ndash4453 2007

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Disease Markers

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OncologyJournal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

14 Scientifica

[108] T N Dechow L Pedranzini A Leitch et al ldquoRequirement ofmatrix metalloproteinase-9 for the transformation of humanmammary epithelial cells by Stat3-Crdquo Proceedings of the Nati-onal Academy of Sciences of the United States of America vol101 no 29 pp 10602ndash10607 2004

[109] S Ito P Ansari M Sakatsume et al ldquoInterleukin-10 inhibitsexpression of both interferon120572- and interferon 120574-induced genesby suppressing tyrosine phosphorylation of STAT1rdquo Blood vol93 no 5 pp 1456ndash1463 1999

[110] HWang J Brown C A Garcia et al ldquoThe role of glycogen syn-thase kinase 3 in regulating IFN-120573-mediated IL-10 productionrdquoJournal of Immunology vol 186 no 2 pp 675ndash684 2011

[111] S Kaur A Sassano A M Joseph et al ldquoDual regulatory rolesof phosphatidylinositol 3-kinase in IFN signalingrdquo Journal ofImmunology vol 181 no 10 pp 7316ndash7323 2008

[112] F Lekmine A Sassano S Uddin et al ldquoInterferon-120574 engagesthe p70 S6 kinase to regulate phosphorylation of the 40S S6ribosomal proteinrdquo Experimental Cell Research vol 295 no 1pp 173ndash182 2004

[113] F Lekmine S Uddin A Sassano et al ldquoActivation of the p70 S6kinase and phosphorylation of the 4E-BP1 repressor of mRNAtranslation by type I interferonsrdquo The Journal of BiologicalChemistry vol 278 no 30 pp 27772ndash27780 2003

[114] Y Li A Sassano B Majchrzak et al ldquoRole of p38120572 mapkinase in type I interferon signalingrdquo The Journal of BiologicalChemistry vol 279 no 2 pp 970ndash979 2004

[115] S Uddin F Lekmine N Sharma et al ldquoThe Rac1p38 mitogen-activated protein kinase pathway is required for interferon 120572-dependent transcriptional activation but not serine phosphory-lation of Stat proteinsrdquoThe Journal of Biological Chemistry vol275 no 36 pp 27634ndash27640 2000

[116] S Uddin B Majchrzak J Woodson et al ldquoActivation of thep38mitogen-activated protein kinase by type I interferonsrdquoTheJournal of Biological Chemistry vol 274 no 42 pp 30127ndash301311999

[117] M David E Petricoin III C Benjamin R Pine M J WeberandAC Larner ldquoRequirement forMAPkinase (ERK2) activityin interferon 120572- and interferon 120573-stimulated gene expressionthrough STAT proteinsrdquo Science vol 269 no 5231 pp 1721ndash1723 1995

[118] H Ishida K Ohkawa A Hosui et al ldquoInvolvement of p38signaling pathway in interferon-120572-mediated antiviral activitytoward hepatitis C virusrdquo Biochemical and Biophysical ResearchCommunications vol 321 no 3 pp 722ndash727 2004

[119] I A Mayer A Verma I M Grumbach et al ldquoThe p38 MAPKpathway mediates the growth inhibitory effects of interferon-120572 in BCR-ABL-expressing cellsrdquo The Journal of Biological Che-mistry vol 276 no 30 pp 28570ndash28577 2001

[120] F Wang Y Ma J W Barrett et al ldquoDisruption of Erk-depe-ndent type I interferon induction breaks the myxoma virusspecies barrierrdquo Nature Immunology vol 5 no 12 pp 1266ndash1274 2004

[121] J-P Herbeuval A Boasso J-C Grivel et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) in HIV-1-infected patientsand its in vitro production by antigen-presenting cellsrdquo Bloodvol 105 no 6 pp 2458ndash2464 2005

[122] J J Kohler D L Tuttle C R Coberley J W Sleasman andM M Goodenow ldquoHuman immunodeficiency virus type 1(HIV-1) induces activation of multiple stats in CD4+ cells oflymphocyte ormonocytemacrophage lineagesrdquo Journal of Leu-kocyte Biology vol 73 no 3 pp 407ndash416 2003

[123] B Renga D Francisci C DrsquoAmore et al ldquoThe HIV matrixprotein p17 subverts nuclear receptors expression and induces aSTAT1-dependent proinflammatory phenotype in monocytesrdquoPLoS ONE vol 7 no 4 Article ID e35924 2012

[124] S E Bosinger Q Li S N Gordon et al ldquoGlobal genomicanalysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeysrdquo Journal of Clinical Investigation vol119 no 12 pp 3556ndash3572 2009

[125] B Jacquelin V Mayau B Targat et al ldquoNonpathogenic SIVinfection of African greenmonkeys induces a strong but rapidlycontrolled type I IFN responserdquo Journal of Clinical Investigationvol 119 no 12 pp 3544ndash3555 2009

[126] N K Dhillon F Peng R M Ransohoff and S Buch ldquoPDGFsynergistically enhances IFN-120574-induced expression of CXCL10in blood-derived macrophages implications for HIV demen-tiardquo Journal of Immunology vol 179 no 5 pp 2722ndash2730 2007

[127] E Masliah E S Roberts D Langford et al ldquoPatterns ofgene dysregulation in the frontal cortex of patients with HIVencephalitisrdquo Journal of Neuroimmunology vol 157 no 1-2 pp163ndash175 2004

[128] N A Khan F Di Cello A Nath and K S Kim ldquoHuman imm-unodeficiency virus type 1 Tat-mediated cytotoxicity of humanbrainmicrovascular endothelial cellsrdquo Journal of NeuroVirologyvol 9 no 6 pp 584ndash593 2003

[129] R L Furler andCHUittenbogaart ldquoSignaling through the P38and ERK pathways a common link between HIV replicationand the immune responserdquo Immunologic Research vol 48 no1ndash3 pp 99ndash109 2010

[130] D Gutierrez-Sanmartin E Varela-Ledo A Aguilera et alldquoImplication of p38 mitogen-activated protein kinase isoforms(120572 120573 120574 and 120575) in CD4+ T-cell infection with human immunod-eficiency virus type 1rdquo Journal of General Virology vol 89 no 7pp 1661ndash1671 2008

[131] R Horie T Ishida M Maruyama-Nagai et al ldquoTRAF activa-tion of CEBP120573 (NF-IL6) via p38 MAPK induces HIV-1 geneexpression inmonocytesmacrophagesrdquoMicrobes and Infectionvol 9 no 6 pp 721ndash728 2007

[132] K Muthumani S A Wadsworth N S Dayes et al ldquoSuppres-sion of HIV-1 viral replication and cellular pathogenesis by anovel p38JNK kinase inhibitorrdquo AIDS vol 18 no 5 pp 739ndash748 2004

[133] L Shapiro K A Heidenreich M K Meintzer and C A Din-arello ldquoRole of p38 mitogen-activated protein kinase in HIVtype 1 production in vitrordquo Proceedings of the National Academyof Sciences of the United States of America vol 95 no 13 pp7422ndash7426 1998

[134] P S Cohen H Schmidtmayerova J Dennis et al ldquoThe criticalrole of p38 MAP kinase in T cell HIV-1 replicationrdquo MolecularMedicine vol 3 no 5 pp 339ndash346 1997

[135] S Kumar M J Orsini J C Lee P C McDonnell C Debouckand P R Young ldquoActivation of the HIV-1 long terminal rep-eat by cytokines and environmental stress requires an activeCSBPp38 MAP kinaserdquo The Journal of Biological Chemistryvol 271 no 48 pp 30864ndash30869 1996

[136] E Jacotot B Krust C Callebaut A G Laurent-Crawford JBlanco and A G Hovanessian ldquoHIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and inde-pendent mechanismsrdquo Apoptosis vol 2 no 1 pp 47ndash60 1997

[137] M Kaul and S A Lipton ldquoChemokines and activated macr-ophages in HIV gp120-induced neuronal apoptosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 96 no 14 pp 8212ndash8216 1999

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 15

[138] C E Rudd ldquoMARKp38 alternative and nonstressful in T cellsrdquoNature Immunology vol 6 no 4 pp 368ndash370 2005

[139] S A Trushin A Algeciras-Schimnich S R Vlahakis et alldquoGlycoprotein 120 binding to CXCR4 causes p38-dependentprimary T cell death that is facilitated by but does not requirecell-associated CD4rdquo Journal of Immunology vol 178 no 8 pp4846ndash4853 2007

[140] A Boasso A W Hardy S A Anderson M J Dolan and GM Shearer ldquoHIV-induced type I interferon and tryptophancatabolism drive T cell dysfunction despite phenotypic activa-tionrdquo PLoS ONE vol 3 no 8 Article ID e2961 2008

[141] X Yang Y M Jiao RWang et al ldquoHigh ccr5 density on centralmemory cd4+ t cells in acute hiv-1 infection is mostly associatedwith rapid disease progressionrdquo PLoS ONE vol 7 Article IDe49526 2012

[142] M Paiardini B Cervasi E Reyes-Aviles et al ldquoLow levels ofSIV infection in sooty mangabey central memory CD4+ T cellsare associated with limited CCR5 expressionrdquoNature Medicinevol 17 no 7 pp 830ndash836 2011

[143] I Pandrea C Apetrei S Gordon et al ldquoPaucity of CD4+CCR5+T cells is a typical feature of natural SIV hostsrdquo Blood vol 109no 3 pp 1069ndash1076 2007

[144] K Fukada Y Sobao H Tomiyama S Oka and M TakiguchildquoFunctional expression of the chemokine receptor CCR5 onvirus epitope-specific memory and effector CD8+ T cellsrdquoJournal of Immunology vol 168 no 5 pp 2225ndash2232 2002

[145] I Pandrea R Onanga S Souquiere et al ldquoPaucity of CD4+CCR5+ T cells may prevent transmission of simian immunod-eficiency virus in natural nonhuman primate hosts by breast-feedingrdquo Journal of Virology vol 82 no 11 pp 5501ndash5509 2008

[146] J-P Herbeuval and G M Shearer ldquoHIV-1 immunopathogene-sis how good interferon turns badrdquo Clinical Immunology vol123 no 2 pp 121ndash128 2007

[147] M Chawla-Sarkar D J Lindner Y-F Liu et al ldquoApoptosis andinterferons role of interferon-stimulated genes as mediators ofapoptosisrdquo Apoptosis vol 8 no 3 pp 237ndash249 2003

[148] H Tamura K Ogata H Dong and L Chen ldquoImmunology ofB7-H1 and its roles in human diseasesrdquo International Journal ofHematology vol 78 no 4 pp 321ndash328 2003

[149] A D Badley D H Dockrell A Algeciras et al ldquoIn vivo analysisof FasFasL interactions in HIV-infected patientsrdquo Journal ofClinical Investigation vol 102 no 1 pp 79ndash87 1998

[150] A M Dyrhol-Riise M Ohlsson K Skarstein et al ldquoT cell pro-liferation and apoptosis in HIV-1-infected lymphoid tis-sue impact of highly active antiretroviral therapyrdquo ClinicalImmunology vol 101 no 2 pp 180ndash191 2001

[151] A M Dyrhol-Riise G Stent B I Roslashsok P Voltersvik JOlofsson and B Asjo ldquoThe FasFasL system and T cell apop-tosis in HIV-1-infected lymphoid tissue during highly activeantiretroviral therapyrdquo Clinical Immunology vol 101 no 2 pp169ndash179 2001

[152] J-P Herbeuval J-C Grivel A Boasso et al ldquoCD4+ T-celldeath induced by infectious and noninfectious HIV-1 role oftype 1 interferon-dependent TRAILDR5-mediated apoptosisrdquoBlood vol 106 no 10 pp 3524ndash3531 2005

[153] G Stary I Klein S Kohlhofer et al ldquoPlasmacytoid dendriticcells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patientsrdquo Blood vol 114 no 18 pp 3854ndash3863 2009

[154] J-P Herbeuval C Lambert O Sabido et al ldquoMacrophagesfrom cancer patients analysis of TRAIL TRAIL receptors andcolon tumor cell apoptosisrdquo Journal of the National Cancer Inst-itute vol 95 no 8 pp 611ndash621 2003

[155] J Chehimi E Papasavvas C Tomescu et al ldquoInability of pla-smacytoid dendritic cells to directly lyse HIV-infected autolo-gous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligandrdquo Journal of Virology vol 84no 6 pp 2762ndash2773 2010

[156] D-M Zhu J Shi S Liu Y Liu and D Zheng ldquoHIV infectionenhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactiveoxygen speciesrdquo PLoS ONE vol 6 no 4 Article ID e18291 2011

[157] D Trabattoni M Saresella M Biasin et al ldquoB7-H1 is up-regulated in HIV infection and is a novel surrogate marker ofdisease progressionrdquo Blood vol 101 no 7 pp 2514ndash2520 2003

[158] L V Riella A M Paterson A H Sharpe and A ChandrakerldquoRole of the pd-1 pathway in the immune responserdquo AmericanJournal of Transplantation vol 12 pp 2575ndash2587 2012

[159] M Larsson E M Shankar K F Che et al ldquoMolecular sign-atures of t-cell inhibition in hiv-1 infectionrdquo Retrovirology vol10 article 31 2013

[160] B E Palmer C P Neff J Lecureux et al ldquoIn vivo blockade ofthe pd-1 receptor suppresses hiv-1 viral loads and improves cd4+t cell levels in humanizedmicerdquoThe Journal of Immunology vol190 pp 211ndash219 2013

[161] B Dai L Xiao P D Bryson J Fang and P Wang ldquoPd-1pd-l1 blockade can enhance hiv-1 gag-specific t cell immunityelicited by dendritic cell-directed lentiviral vaccinesrdquoMolecularTherapy vol 20 pp 1800ndash1809 2012

[162] R D Shetty V Velu K Titanji et al ldquoPD-1 blockade during chr-onic SIV infection reduces hyperimmune activation andmicro-bial translocation in rhesus macaquesrdquo Journal of ClinicalInvestigation vol 122 no 5 pp 1712ndash1716 2012

[163] F Porichis D S Kwon J Zupkosky et al ldquoResponsiveness ofHIV-specific CD4 T cells to PD-1 blockaderdquo Blood vol 118 no4 pp 965ndash974 2011

[164] B J Macatangay and C R Rinaldo ldquoPd-1 blockade a promisingimmunotherapy for hivrdquo Cellscience vol 5 pp 61ndash65 2009

[165] A Takaoka S Hayakawa H Yanai et al ldquoIntegration ofinterferon-120572120573 signalling to p53 responses in tumour suppres-sion and antiviral defencerdquo Nature vol 424 no 6948 pp 516ndash523 2003

[166] G Doitsh M Cavrois K G Lassen et al ldquoAbortive HIVinfection mediates CD4 T cell depletion and inflammation inhuman lymphoid tissuerdquo Cell vol 143 no 5 pp 789ndash801 2010

[167] A J Sadler and B R G Williams ldquoInterferon-inducible anti-viral effectorsrdquo Nature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[168] T Takeuchi S Iwahara Y Saeki H Sasajima andH YokosawaldquoLink between the ubiquitin conjugation system and the ISG15conjugation system ISG15 conjugation to the UbcH6 ubiquitinE2 enzymerdquo Journal of Biochemistry vol 138 no 6 pp 711ndash7192005

[169] C Zhao S L Beaudenon M L Kelley et al ldquoThe UbcH8 ubiq-uitin E2 enzyme is also the E2 enzyme for ISG15 an IFN-120572120573-induced ubiquitin-like proteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no20 pp 7578ndash7582 2004

[170] W Yuan and R M Krug ldquoInfluenza B virus NS1 protein inhi-bits conjugation of the interferon (IFN)-induced ubiquitin-likeISG15 proteinrdquo The EMBO Journal vol 20 no 3 pp 362ndash3712001

[171] G Lu J T Reinert I Pitha-Rowe et al ldquoISG15 enhances theinnate antiviral response by inhibition of IRF-3 degradationrdquoCellular and Molecular Biology vol 52 no 1 pp 29ndash41 2006

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

16 Scientifica

[172] T Takeuchi T Kobayashi S Tamura and H Yokosawa ldquoNeg-ative regulation of protein phosphatase 2C120573 by ISG15 conjuga-tionrdquo FEBS Letters vol 580 no 18 pp 4521ndash4526 2006

[173] MWWoods J N Kelly C J Hattlmann et al ldquoHumanHERC5restricts an early stage ofHIV-1 assembly by amechanism corre-lating with the ISGylation of Gagrdquo Retrovirology vol 8 article95 2011

[174] AOkumura G Lu I Pitha-Rowe and PM Pitha ldquoInnate anti-viral response targets HIV-1 release by the induction of ubi-quitin-like protein ISG15rdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 5 pp1440ndash1445 2006

[175] J D MacMicking ldquoIFN-inducible GTPases and immunity tointracellular pathogensrdquo Trends in Immunology vol 25 no 11pp 601ndash609 2004

[176] O Haller H Arnheiter J Lindenmann and I Gresser ldquoHostgene influences sensitivity to interferon action selectively forinfluenza virusrdquo Nature vol 283 no 5748 pp 660ndash662 1980

[177] C Goujon O Moncorge H Bauby et al ldquoHuman mx2 isan interferon-induced post-entry inhibitor of hiv-1 infectionrdquoNature vol 502 pp 559ndash562 2013

[178] Z Liu Q Pan S Ding et al ldquoThe interferon-induciblemxb pro-tein inhibits hiv-1 infectionrdquo Cell Host amp Microbe vol 14 pp398ndash410 2013

[179] D Rebouillat and A G Hovanessian ldquoThe human 2rsquo5rsquo-oligo-adenylate synthetase family interferon-induced proteins withunique enzymatic propertiesrdquo Journal of Interferon and Cyto-kine Research vol 19 no 4 pp 295ndash308 1999

[180] I M Kerr R E Brown and A G Hovanessian ldquoNature ofinhibitor of cell-free protein synthesis formed in response tointerferon and double-stranded RNArdquo Nature vol 268 no5620 pp 540ndash542 1977

[181] M J Clemens andCMVaquero ldquoInhibition of protein synthe-sis by double-stranded RNA in reticulocyte lysates evidence foractivation of an endoribonucleaserdquo Biochemical and BiophysicalResearch Communications vol 83 no 1 pp 59ndash68 1978

[182] K Malathi B Dong M Gale Jr and R H Silverman ldquoSmallself-RNA generated by RNase L amplifies antiviral innateimmunityrdquo Nature vol 448 no 7155 pp 816ndash819 2007

[183] R KMaitra and R H Silverman ldquoRegulation of human immu-nodeficiency virus replication by 2101584051015840- oligoadenylate-depe-ndent RNase Lrdquo Journal of Virology vol 72 no 2 pp 1146ndash11521998

[184] W K Roberts A Hovanessian and R E Brown ldquoInterferonmediated protein kinase and low molecular weight inhibitor ofprotein synthesisrdquoNature vol 264 no 5585 pp 477ndash480 1976

[185] D R Taylor S B Lee P R Romano et al ldquoAutophosphorylationsites participate in the activation of the double- stranded-RNA-activated protein kinase PKRrdquo Molecular and Cellular Biologyvol 16 no 11 pp 6295ndash6302 1996

[186] P R Romano M T Garcia-Barrio X Zhang et al ldquoAutophos-phorylation in the activation loop is required for full kinaseactivity in vivo of human and yeast eukaryotic initiation factor2120572 kinases PKR andGCN2rdquoMolecular andCellular Biology vol18 no 4 pp 2282ndash2297 1998

[187] M Dey C Cao A C Dar et al ldquoMechanistic link betweenPKR dimerization autophosphorylation and eIF2120572 substraterecognitionrdquo Cell vol 122 no 6 pp 901ndash913 2005

[188] A C Dar T E Dever and F Sicheri ldquoHigher-order substraterecognition of eIF2120572 by the RNA-dependent protein kinasePKRrdquo Cell vol 122 no 6 pp 887ndash900 2005

[189] S Nanduri B W Carpick Y Yang B R G Williams and JQin ldquoStructure of the double-stranded RNA-binding domainof the protein kinase PKR reveals the molecular basis of itsdsRNA-mediated activationrdquoThe EMBO Journal vol 17 no 18pp 5458ndash5465 1998

[190] S R Nallagatla J Hwang R Toroney X Zheng C E Cameronand P C Bevilacqua ldquo51015840-triphosphate-dependent activation ofPKR by RNAswith short stem-loopsrdquo Science vol 318 no 5855pp 1455ndash1458 2007

[191] M E Adelson C Martinand-Mari K T Iacono N F Mutoand R J Suhadolnik ldquoInhibition of human immunodeficiencyvirus (HIV-1) replication in SupT1 cells transduced with anHIV-1 LTR-driven PKR cDNA constructrdquo European Journal ofBiochemistry vol 264 no 3 pp 806ndash815 1999

[192] G Clerzius J-F Gelinas A Daher M Bonnet E F Meurs andA Gatignol ldquoADAR1 interacts with PKR during human imm-unodeficiency virus infection of lymphocytes and contributes toviral replicationrdquo Journal of Virology vol 83 no 19 pp 10119ndash10128 2009

[193] D I Dimitrova X Yang N L Reichenbach et al ldquoLentivirus-mediated transduction of PKR into CD34+ hematopoietic stemcells inhibits HIV-1 replication in differentiated T cell progenyrdquoJournal of Interferon and Cytokine Research vol 25 no 6 pp345ndash360 2005

[194] A Daher M Longuet D Dorin et al ldquoTwo dimerization dom-ains in the trans-activation response RNA-binding protein(TRBP) individually reverse the protein kinase R inhibition ofHIV-1 long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 276 no 36 pp 33899ndash33905 2001

[195] M Benkirane C Neuveut R F Chun et al ldquoOncogenicpotential of TAR RNA binding protein TRBP and its regulatoryinteraction with RNA-dependent protein kinase PKRrdquo TheEMBO Journal vol 16 no 3 pp 611ndash624 1997

[196] N F Muto C Martinand-Mari M E Adelson and R J Suha-dolnik ldquoInhibition of replication of reactivated human immun-odeficiency virus type 1 (HIV-1) in latently infected U1 cellstransduced with an HIV-1 long terminal repeat-driven PKRcDNA constructrdquo Journal of Virology vol 73 no 11 pp 9021ndash9028 1999

[197] S Bannwarth and A Gatignol ldquoHIV-1 TAR RNA the target ofmolecular interactions between the virus and its hostrdquo CurrentHIV Research vol 3 no 1 pp 61ndash71 2005

[198] D DorinM C Bonnet S Bannwarth A Gatignol E F Meursand C Vaquero ldquoThe TAR RNA-binding protein TRBP stim-ulates the expression of TAR-containing RNAs in vitro andin vivo independently of its ability to inhibit the dsRNA-dependent kinase PKRrdquoThe Journal of Biological Chemistry vol278 no 7 pp 4440ndash4448 2003

[199] A Gatignol ldquoTranscription of HIV tat and cellular chromatinrdquoAdvances in Pharmacology vol 55 pp 137ndash159 2007

[200] B W Carpick V Graziano D Schneider R K Maitra X Leeand B R G Williams ldquoCharacterization of the solution com-plex between the interferon-induced double-stranded RNA-activated protein kinase and HIV-I trans-activating regionRNArdquo The Journal of Biological Chemistry vol 272 no 14 pp9510ndash9516 1997

[201] I Kim CW Liu and J D Puglisi ldquoSpecific Recognition of HIVTAR RNA by the dsRNA Binding Domains (dsRBD1-dsRBD2)of PKRrdquo Journal of Molecular Biology vol 358 no 2 pp 430ndash442 2006

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 17

[202] R K Maitra N A J McMillan S Desai et al ldquoHIV-1 TARRNA has an intrinsic ability to activate interferon-inducibleenzymesrdquo Virology vol 204 no 2 pp 823ndash827 1994

[203] A Reymond G Meroni A Fantozzi et al ldquoThe tripartite motiffamily identifies cell compartmentsrdquoTheEMBO Journal vol 20no 9 pp 2140ndash2151 2001

[204] S D Barr J R Smiley and F D Bushman ldquoThe interferon res-ponse inhibits HIV particle production by induction ofTRIM22rdquo PLoS Pathogens vol 4 no 2 2008

[205] M Stremlau C M Owens M J Perron M Kiessling P Auti-ssier and J Sodroski ldquoThe cytoplasmic body componentTRIM5120572 restricts HIV-1 infection in old world monkeysrdquo Nat-ure vol 427 no 6977 pp 848ndash853 2004

[206] MW Yap S Nisole C Lynch and J P Stoye ldquoTRIM5120572 proteinrestricts both HIV-1 and murine leukemia virusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 29 pp 10786ndash10791 2004

[207] M G Grutter and J Luban ldquoTRIM5 structure HIV-1 capsidrecognition and innate immune signalingrdquo Current Opinion inVirology vol 2 no 2 pp 142ndash150 2012

[208] L Carthagena A Bergamaschi JM Luna et al ldquoHumanTRIMgene expression in response to interferonsrdquo PLoS ONE vol 4no 3 Article ID e4894 2009

[209] J Luban ldquoCyclophilin A TRIM5 and resistance to humanimmunodeficiency virus type 1 infectionrdquo Journal of Virologyvol 81 no 3 pp 1054ndash1061 2007

[210] M Lienlaf F Hayashi F Di Nunzio et al ldquoContribution ofE3-ubiquitin ligase activity to HIV-1 restriction by TRIM5120572rhstructure of the RING domain of TRIM5120572rdquo Journal of Virologyvol 85 no 17 pp 8725ndash8737 2011

[211] T Pertel S Hausmann D Morger et al ldquoTRIM5 is an innateimmune sensor for the retrovirus capsid latticerdquo Nature vol472 no 7343 pp 361ndash365 2011

[212] C OrsquoConnor T Pertel S Gray et al ldquop62sequestosome-1associates with and sustains the expression of retroviral rest-riction factor TRIM5120572rdquo Journal of Virology vol 84 no 12 pp5997ndash6006 2010

[213] C J Rold and C Aiken ldquoProteasomal degradation of TRIM5120572during retrovirus restrictionrdquo PLoS Pathogens vol 4 no 5Article ID e1000074 2008

[214] Z Lukic S Hausmann S Sebastian et al ldquoTRIM5alpha asso-ciates with proteasomal subunits in cells while in complex withHIV-1 virionsrdquo Retrovirology vol 8 article 93 2011

[215] A J Price F Marzetta M Lammers et al ldquoActive site remodel-ing switches HIV specificity of antiretroviral TRIMCyprdquoNatureStructural and Molecular Biology vol 16 no 10 pp 1036ndash10422009

[216] G J Towers T Hatziioannou S Cowan S P Goff J Luban andP D Bieniasz ldquoCyclophilin Amodulates the sensitivity of HIV-1 to host restriction factorsrdquo Nature Medicine vol 9 no 9 pp1138ndash1143 2003

[217] W Hofmann D Schubert J LaBonte et al ldquoSpecies-specificpostentry barriers to primate immunodeficiency virus infec-tionrdquo Journal of Virology vol 73 no 12 pp 10020ndash10028 1999

[218] M Stremlau M Perron M Lee et al ldquoSpecific recognitionand accelerated uncoating of retroviral capsids by the TRIM5120572restriction factorrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 14 pp 5514ndash5519 2006

[219] E Sokolskaja L Berthoux and J Luban ldquoCyclophilin A andTRIM5120572 independently regulate human immunodeficiency

virus type 1 infectivity in human cellsrdquo Journal of Virology vol80 no 6 pp 2855ndash2862 2006

[220] E Battivelli D Lecossier SMatsuoka JMigraine F Clavel andA J Hance ldquoStrain-specific differences in the impact of humanTRIM5120572 differentTRIM5120572 alleles and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1rdquo Journal ofVirology vol 84 no 21 pp 11010ndash11019 2010

[221] A Kirmaier F Wu R M Newman et al ldquoTRIM5 suppressescross-species transmission of a primate immunodeficiencyvirus and selects for emergence of resistant variants in the newspeciesrdquo PLoS Biology vol 8 no 8 pp 35ndash36 2010

[222] S-Y Lim T Chan R S Gelman et al ldquoContributions ofMamu-Alowast01 status and TRIM5 allele expression but not CCL3L copynumber variation to the control of SIVmac251 replication inIndian-origin rhesus monkeysrdquo PLoS genetics vol 6 no 6 pe1000997 2010

[223] S-Y Lim T Rogers T Chan et al ldquoTRIM5120572 modulatesimmunodeficiency virus control in rhesus monkeysrdquo PLoSPathogens vol 6 no 1 Article ID e1000738 2010

[224] M R Reynolds J B Sacha A M Weiler et al ldquoThe TRIM5120572genotype of rhesus macaques affects acquisition of simianimmunodeficiency virus SIVsmE660 infection after repeatedlimiting-dose intrarectal challengerdquo Journal of Virology vol 85no 18 pp 9637ndash9640 2011

[225] W W Yeh S S Rao S-Y Lim et al ldquoThe TRIM5 gene mod-ulates penile mucosal acquisition of simian immunodeficiencyvirus in rhesus monkeysrdquo Journal of Virology vol 85 no 19 pp10389ndash10398 2011

[226] F-L Liu Y-Q Qiu H Li et al ldquoAn HIV-1 resistance polymor-phism inTRIM5120572 gene amongChinese intravenous drug usersrdquoJournal of Acquired Immune Deficiency Syndromes vol 56 no4 pp 306ndash311 2011

[227] H Price P Lacap J Tuff et al ldquoA TRIM5120572 exon 2 polymor-phism is associated with protection fromHIV-1 infection in thePumwani sex worker cohortrdquo AIDS vol 24 no 12 pp 1813ndash1821 2010

[228] S Sewram R Singh E Kormuth et al ldquoHuman TRIM5120572 exp-ression levels and reduced susceptibility to HIV-I infectionrdquoJournal of Infectious Diseases vol 199 no 11 pp 1657ndash16632009

[229] D Van Manen M A N Rits C Beugeling K Van Dort HSchuitemaker and N A Kootstra ldquoThe effect of TRIM5 poly-morphisms on the clinical course of HIV-1 infectionrdquo PLoSPathogens vol 4 no 2 2008

[230] E Battivelli J Migraine D Lecossier P Yeni F Clavel and AJ Hance ldquoGag cytotoxic T lymphocyte escape mutations canincrease sensitivity of HIV-1 to human TRIM5120572 linking intr-insic and acquired immunityrdquo Journal of Virology vol 85 no22 pp 11846ndash11854 2011

[231] S U Tareen andM Emerman ldquoHumanTRIM5120572 has additionalactivities that are uncoupled from retroviral capsid recognitionrdquoVirology vol 409 no 1 pp 113ndash120 2011

[232] A Bouazzaoui M Kreutz V Eisert et al ldquoStimulated trans-acting factor of 50 kDa (Staf50) inhibits HIV-1 replication inhumanmonocyte-derived macrophagesrdquo Virology vol 356 no1-2 pp 79ndash94 2006

[233] C Tissot andNMechti ldquoMolecular cloning of a new interferon-induced factor that represses human immunodeficiency virustype I long terminal repeat expressionrdquoThe Journal of BiologicalChemistry vol 270 no 25 pp 14891ndash14898 1995

[234] A Kajaste-Rudnitski S S Marelli C Pultrone et al ldquoTRIM22inhibits HIV-1 transcription independently of Its E3 ubiquitin

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

18 Scientifica

ligase activity Tat and NF-120581B-responsive long terminal repeatelementsrdquo Journal of Virology vol 85 no 10 pp 5183ndash5196 2011

[235] A M Sheehy N C Gaddis J D Choi and M H Malim ldquoIso-lation of a human gene that inhibits HIV-1 infection and issuppressed by the viral Vif proteinrdquo Nature vol 418 no 6898pp 646ndash650 2002

[236] L Chelico P Pham P Calabrese and M F GoodmanldquoAPOBEC3GDNAdeaminase acts processively 31015840 rarr 51015840 on sin-gle-stranded DNArdquo Nature Structural and Molecular Biologyvol 13 no 5 pp 392ndash399 2006

[237] R S Harris K N Bishop A M Sheehy et al ldquoDNA deamina-tionmediates innate immunity to retroviral infectionrdquoCell vol113 no 6 pp 803ndash809 2003

[238] Q Yu R Konig S Pillai et al ldquoSingle-strand specificity ofAPOBEC3G accounts for minus-strand deamination of theHIV genomerdquo Nature Structural and Molecular Biology vol 11no 5 pp 435ndash442 2004

[239] M-A Langlois and M S Neuberger ldquoHuman APOBEC3G canrestrict retroviral infection in avian cells and acts independentlyof bothUNG and SMUG1rdquo Journal of Virology vol 82 no 9 pp4660ndash4664 2008

[240] K N Bishop M Verma E-Y Kim S M Wolinsky and M HMalim ldquoAPOBEC3G inhibits elongation of HIV-1 reverse tra-nscriptsrdquo PLoS Pathogens vol 4 no 12 Article ID e10002312008

[241] Y Iwatani D S B Chan F Wang et al ldquoDeaminase-indepen-dent inhibition of HIV-1 reverse transcription by APOBEC3GrdquoNucleic Acids Research vol 35 no 21 pp 7096ndash7108 2007

[242] H P Bogerd and B R Cullen ldquoSingle-stranded RNA facilitatesnucleocapsid APOBEC3G complex formationrdquo RNA vol 14no 6 pp 1228ndash1236 2008

[243] B Mangeat P Turelli G Caron M Friedli L Perrin and DTrono ldquoBroad antiretroviral defence by human APOBEC3Gthrough lethal editing of nascent reverse transcriptsrdquo Naturevol 424 no 6944 pp 99ndash103 2003

[244] X Yu Y Yu B Liu et al ldquoInduction of APOBEC3G ubiquiti-nation and degradation by an HIV-1 Vif-Cul5-SCF complexrdquoScience vol 302 no 5647 pp 1056ndash1060 2003

[245] H Zhang B Yang R J Pomerantz C Zhang S C Arunacha-lam and L Gao ldquoThe cytidine deaminase CEM15 induceshypermutation in newly synthesized HIV-1 DNArdquo Nature vol424 no 6944 pp 94ndash98 2003

[246] M Marin K M Rose S L Kozak and D Kabat ldquoHIV-1 Vifprotein binds the editing enzyme APOBEC3G and induces itsdegradationrdquo Nature Medicine vol 9 no 11 pp 1398ndash14032003

[247] A M Sheehy N C Gaddis and M H Malim ldquoThe antiretro-viral enzyme APOBEC3G is degraded by the proteasome inresponse to HIV-1 VifrdquoNature Medicine vol 9 no 11 pp 1404ndash1407 2003

[248] K Stopak C De Noronha W Yonemoto and W C GreeneldquoHIV-1 Vif blocks the antiviral activity of APOBEC3G byimpairing both its translation and intracellular stabilityrdquoMolec-ular Cell vol 12 no 3 pp 591ndash601 2003

[249] J S Albin and R S Harris ldquoInteractions of host APOBEC3restriction factors with HIV-1 in vivo implications for thera-peuticsrdquo Expert reviews in molecular medicine vol 12 articl e42010

[250] S Kupzig V Korolchuk R Rollason A Sugden A Wilde andG Banting ldquoBst-2HM124 is a raft-associated apicalmembraneproteinwith an unusual topologyrdquoTraffic vol 4 no 10 pp 694ndash709 2003

[251] S J D Neil S W Eastman N Jouvenet and P D BieniaszldquoHIV-1 vpu promotes release and prevents endocytosis ofnascent retrovirus particles from the plasma membranerdquo PLoSpathogens vol 2 no 5 article e39 2006

[252] N Van Damme D Goff C Katsura et al ldquoThe interferon-induced protein BST-2 restricts HIV-1 release and is downreg-ulated from the cell surface by the viral vpu proteinrdquo Cell Hostand Microbe vol 3 no 4 pp 245ndash252 2008

[253] N Jouvenet S J D Neil M Zhadina et al ldquoBroad-spectruminhibition of retroviral and filoviral particle release by tetherinrdquoJournal of Virology vol 83 no 4 pp 1837ndash1844 2009

[254] P Bates R L Kaletsky J R Francica and C Agrawal-GamseldquoTetherin-mediated restriction of filovirus budding is antago-nized by the Ebola glycoproteinrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 106 no8 pp 2886ndash2891 2009

[255] M Mansouri K Viswanathan J L Douglas et al ldquoMolecularmechanism of BST2tetherin downregulation by K5MIR2 ofKaposirsquos sarcoma-associated herpesvirusrdquo Journal of Virologyvol 83 no 19 pp 9672ndash9681 2009

[256] D Perez-Caballero T Zang A Ebrahimi et al ldquoTetherininhibits HIV-1 release by directly tethering virions to cellsrdquoCellvol 139 no 3 pp 499ndash511 2009

[257] M Dube B B Roy P Guiot-Guillain et al ldquoAntagonism oftetherin restriction of HIV-1 release by vpu involves bindingand sequestration of the restriction factor in a perinuclearcompartmentrdquo PLoS pathogens vol 6 no 4 p e1000856 2010

[258] R S Mitchell C Katsura M A Skasko et al ldquoVpu antagonizesBST-2-mediated restriction of HIV-1 release via 120573-TrCP andendo-lysosomal traffickingrdquo PLoS Pathogens vol 5 no 5Article ID e1000450 2009

[259] E Bartee A McCormack and K Fruh ldquoQuantitative mem-brane proteomics reveals new cellular targets of viral immunemodulatorsrdquo PLoS pathogens vol 2 no 10 article e107 2006

[260] J L Douglas K Viswanathan M N McCarroll J K GustinK Fruh and A V Moses ldquoVpu directs the degradation of thehuman immunodeficiency virus restriction factor BST-2tet-herin via a 120573TrCP-dependent mechanismrdquo Journal of Virologyvol 83 no 16 pp 7931ndash7947 2009

[261] E Miyagi A J Andrew S Kao and K Strebe ldquoVpu enhancesHIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 106 no 8 pp 2868ndash2873 2009

[262] B Jia R Serra-Moreno W Neidermyer Jr et al ldquoSpecies-spe-cific activity of SIVNef andHIV-1 vpu in overcoming restrictionby tetherinBST2rdquo PLoS Pathogens vol 5 no 5 Article IDe1000429 2009

[263] F Zhang S J Wilson W C Landford et al ldquoNef proteins fromsimian immunodeficiency viruses are tetherin antagonistsrdquoCellHost and Microbe vol 6 no 1 pp 54ndash67 2009

[264] R K Gupta P Mlcochova A Pelchen-Matthews et al ldquoSimianimmunodeficiency virus envelope glycoprotein counteractstetherinBST-2CD317 by intracellular sequestrationrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 49 pp 20889ndash20894 2009

[265] A Le Tortorec and S J D Neil ldquoAntagonism to and intracellularsequestration of human tetherin by the human immunodefi-ciency virus type 2 envelope glycoproteinrdquo Journal of Virologyvol 83 no 22 pp 11966ndash11978 2009

[266] D Ayinde C Maudet C Transy and F Margottin-Goguet ldquoLi-melight on two HIVSIV accessory proteins in macrophage

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Scientifica 19

infection is Vpx overshadowing Vprrdquo Retrovirology vol 7article 35 2010

[267] C Goujon L Jarrosson-Wuilleme J Bernaud D Rigal J-LDarlix and A Cimarelli ldquoWith a little help from a friendincreasing HIV transduction of monocyte-derived dendriticcells with virion-like particles of SIVMACrdquo Gene Therapy vol13 no 12 pp 991ndash994 2006

[268] N Sunseri M OrsquoBrien N Bhardwaj and N R LandauldquoHuman immunodeficiency virus type 1 modified to packageSimian immunodeficiency virus Vpx efficiently infects mac-rophages and dendritic cellsrdquo Journal of virology vol 85 no 13pp 6263ndash6274 2011

[269] M Fujita M Otsuka M Miyoshi B Khamsri M Nomaguchiand A Adachi ldquoVpx is critical for reverse transcription ofthe human immunodeficiency virus type 2 genome in macro-phagesrdquo Journal of Virology vol 82 no 15 pp 7752ndash7756 2008

[270] K Hrecka C Hao M Gierszewska et al ldquoVpx relieves inhi-bition of HIV-1 infection of macrophages mediated by theSAMHD1 proteinrdquoNature vol 474 no 7353 pp 658ndash661 2011

[271] N Laguette B Sobhian N Casartelli et al ldquoSAMHD1 is thedendritic- and myeloid-cell-specific HIV-1 restriction factorcounteracted by Vpxrdquo Nature vol 474 no 7353 pp 654ndash6572011

[272] S Srivastava S K Swanson N Manel L Florens M P Wash-burn and J Skowronski ldquoLentiviral Vpx accessory factor targetsVprBPDCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligaseto enable macrophage infectionrdquo PLoS Pathogens vol 4 no 5Article ID e1000059 2008

[273] A Bergamaschi D Ayinde A David et al ldquoThe human imm-unodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1DCAF1 ubiquitin ligase to overcome a postentry block inmacrophage infectionrdquo Journal of Virology vol 83 no 10 pp4854ndash4860 2009

[274] D C Goldstone V Ennis-Adeniran J J Hedden et al ldquoHIV-1restriction factor SAMHD1 is a deoxynucleoside triphosphatetriphosphohydrolaserdquo Nature vol 480 no 7377 pp 379ndash3822011

[275] H Lahouassa W Daddacha H Hofmann et al ldquoSAMHD1restricts the replication of human immunodeficiency virus type1 by depleting the intracellular pool of deoxynucleoside trip-hosphatesrdquoNature Immunology vol 13 no 3 pp 223ndash228 2012

[276] A Brandariz-Nunez J C Valle-Casuso T E White et al ldquoRoleof samhd1 nuclear localization in restriction of hiv-1 and siv-macrdquo Retrovirology vol 9 article 49 2012

[277] A Goncalves E Karayel G I Rice et al ldquoSamhd1 is a nuc-leic-acid binding protein that ismislocalized due to aicardi-gou-tieres syndrome-associated mutationsrdquo Human Mutation vol33 pp 1116ndash1122 2012

[278] G I Rice J Bond A Asipu et al ldquoMutations involved in Ai-cardi-Goutieres syndrome implicate SAMHD1 as regulator ofthe innate immune responserdquoNature Genetics vol 41 no 7 pp829ndash832 2009

[279] A Berger A F R Sommer J Zwarg et al ldquoSAMHD1-deficientCD14+ cells from individuals with Aicardi-Goutieres syndromeare highly susceptible to HIV-1 infectionrdquo PLoS Pathogens vol7 no 12 Article ID e1002425 2011

[280] N Li W Zhang and X Cao ldquoIdentification of human homo-logue of mouse IFN-120574 induced protein from human dendriticcellsrdquo Immunology Letters vol 74 no 3 pp 221ndash224 2000

[281] P Blanco A K Palucka M Gill V Pascual and J BanchereauldquoInduction of dendritic cell differentiation by IFN-120572 in systemic

lupus erythematosusrdquo Science vol 294 no 5546 pp 1540ndash15432001

[282] S M Santini C Lapenta M Logozzi et al ldquoType I interferonas a powerful adjuvant for monocyte-derived dendritic celldevelopment and activity in vitro and in Hu-PBL-SCID micerdquoJournal of Experimental Medicine vol 191 no 10 pp 1777ndash17882000

[283] S Gallucci M Lolkema and P Matzinger ldquoNatural adjuvantsendogenous activators of dendritic cellsrdquo Nature Medicine vol5 no 11 pp 1249ndash1255 1999

[284] R L Paquette N C Hsu S M Kiertscher et al ldquoInterferon-120572 and granulocyte-macrophage colony-stimulating factor dif-ferentiate peripheral blood monocytes into potent antigen-presenting cellsrdquo Journal of Leukocyte Biology vol 64 no 3 pp358ndash367 1998

[285] A C Larner E F Petricoin Y Nakagawa and D S FinbloomldquoIL-4 attenuates the transcriptional activation of both IFN-120572-and IFN- 120574-induced cellular gene expression in monocytes andmonocytic cell linesrdquo Journal of Immunology vol 150 no 5 pp1944ndash1950 1993

[286] C Wang H M Al-Omar L Radvanyi et al ldquoClonal hetero-geneity of dendritic cells derived from patients with chronicmyeloid leukemia and enhancement of their T-cells stimulatoryactivity by IFN-120572rdquo Experimental Hematology vol 27 no 7 pp1176ndash1184 1999

[287] E Padovan G C Spagnoli M Ferrantini and M HebererldquoIFN-1205722a induces IP-10CXCL10 and MIGCXCL9 productioninmonocyte-derived dendritic cells and enhances their capacityto attract and stimulate CD8+ effector T cellsrdquo Journal ofLeukocyte Biology vol 71 no 4 pp 669ndash676 2002

[288] F Mattei G Schiavoni F Belardelli and D F Tough ldquoIL-15 isexpressed by dendritic cells in response to type I IFN double-stranded RNA or lipopolysaccharide and promotes dendriticcell activationrdquo Journal of Immunology vol 167 no 3 pp 1179ndash1187 2001

[289] T Ito R Amakawa M Inaba S Ikehara K Inaba and S Fuk-uhara ldquoDifferential regulation of human blood dendritic cellsubsets by IFNsrdquo Journal of Immunology vol 166 no 5 pp2961ndash2969 2001

[290] M Lehner T Felzmann K Clodi and W Holter ldquoType Iinterferons in combination with bacterial stimuli induce apop-tosis of monocyte-derived dendritic cellsrdquo Blood vol 98 no 3pp 736ndash742 2001

[291] M B Litinskiy B Nardelli D M Hilbert et al ldquoDCs induceCD40-independent immunoglobulin class switching throughBLyS and APRILrdquo Nature Immunology vol 3 no 9 pp 822ndash829 2002

[292] B LMcRae R T SemnaniM PHayes andGAVan SeventerldquoType I IFNs inhibit human dendritic cell IL-12 production andTh1 cell developmentrdquo Journal of Immunology vol 160 no 9pp 4298ndash4304 1998

[293] E J Bartholome F Willems A Crusiaux K Thielemans LSchandene andM Goldman ldquoIFN-120573 interferes with the differ-entiation of dendritic cells from peripheral blood mononuclearcells selective inhibition of CD40-dependent interleukin-12secretionrdquo Journal of Interferon and Cytokine Research vol 19no 5 pp 471ndash478 1999

[294] B L McRae B A Beilfuss and G A Van Seventer ldquoIFN-120573 differentially regulates CD40-induced cytokine secretion byhuman dendritic cellsrdquo Journal of Immunology vol 164 no 1pp 23ndash28 2000

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

20 Scientifica

[295] P Kalinski J H N Schuitemaker C M U Hilkens E AWierenga and M L Kapsenberg ldquoFinal maturation of den-dritic cells is associated with impaired responsiveness to IFN-120574and to bacterial IL-12 inducers decreased ability of mature den-dritic cells to produce IL-12 during the interactionwithThcellsrdquoJournal of Immunology vol 162 no 6 pp 3231ndash3236 1999

[296] A Langenkamp M Messi A Lanzavecchia and F SallustoldquoKinetics of dendritic cell activation impact on priming ofTH1TH2 and nonpolarized T cellsrdquo Nature Immunology vol1 no 4 pp 311ndash316 2000

[297] C H Kim and H E Broxmeyer ldquoChemokines signal lamps fortrafficking of T and B cells for development and effector fun-ctionrdquo Journal of Leukocyte Biology vol 65 no 1 pp 6ndash15 1999

[298] S Parlato S M Santini C Lapenta et al ldquoExpression ofCCR-7 MIP-3120573 and Th-1 chemokines in type I IFN-inducedmonocyte-derived dendritic cells importance for the rapidacquisition of potentmigratory and functional activitiesrdquoBloodvol 98 no 10 pp 3022ndash3029 2001

[299] S J Szabo B M Sullivan C Sternmann A R Satoskar B PSleckman and L H Glimcher ldquoDistinct effects of T-bet in Th1lineage commitment and IFN-120574 production in CD4 and CD8 Tcellsrdquo Science vol 295 no 5553 pp 338ndash342 2002

[300] S S Cho C M Bacon C Sudarshan et al ldquoActivation ofSTAT4 by IL-12 and IFN-120572 evidence for the involvement ofligand-induced tyrosine and serine phosphorylationrdquo Journal ofImmunology vol 157 no 11 pp 4781ndash4789 1996

[301] L Rogge D DrsquoAmbrosio M Biffi et al ldquoThe role of Stat4 inspecies-specific regulation of Th cell development by type IIFNsrdquo Journal of Immunology vol 161 no 12 pp 6567ndash65741998

[302] L S Berenson J D Farrar T L Murphy and K M MurphyldquoFrontline absence of functional STAT4 activation despitedetectable tyrosine phosphorylation induced bymurine IFN-120572rdquoEuropean Journal of Immunology vol 34 no 9 pp 2365ndash23742004

[303] L S Berenson M Gavrieli J D Farrar T L Murphy and KMMurphy ldquoDistinct characteristics of murine STAT4 activationin response to IL-12 and IFN-120572rdquo Journal of Immunology vol177 no 8 pp 5195ndash5203 2006

[304] J P Huber and J David Farrar ldquoRegulation of effector andmemory T-cell functions by type I interferonrdquo Immunology vol132 no 4 pp 466ndash474 2011

[305] S Matikainen A Paananen M Miettinen et al ldquoIfn-alphaand il-18 synergistically enhance ifn-gamma production inhuman nk cells differential regulation of stat4 activation andifn-gamma gene expression by ifn-alpha and il-12rdquo EuropeanJournal of Immunology vol 31 pp 2236ndash2245 2001

[306] M Strengell I Julkunen and S Matikainen ldquoIFN-120572 regulatesIL-21 and IL-21R expression in human NK and T cellsrdquo Journalof Leukocyte Biology vol 76 no 2 pp 416ndash422 2004

[307] L E Harrington R D Hatton P R Mangan et al ldquoInterleukin17-producing CD4+ effector T cells develop via a lineage distinctfrom the T helper type 1 and 2 lineagesrdquo Nature Immunologyvol 6 no 11 pp 1123ndash1132 2005

[308] A RMoschen S Geiger I Krehan A Kaser andH Tilg ldquoInte-rferon-alpha controls IL-17 expression in vitro and in vivordquoImmunobiology vol 213 no 9-10 pp 779ndash787 2008

[309] L JThompson G A Kolumam SThomas and KMurali-Kri-shna ldquoInnate inflammatory signals induced by various path-ogens differentially dictate the IFN-I dependence of CD8 Tcells for clonal expansion and memory formationrdquo Journal ofImmunology vol 177 no 3 pp 1746ndash1754 2006

[310] G A Kolumam S Thomas L J Thompson J Sprent and KMurali-Krishna ldquoType I interferons act directly on CD8 T cellsto allow clonal expansion andmemory formation in response toviral infectionrdquo Journal of Experimental Medicine vol 202 no5 pp 637ndash650 2005

[311] J M Curtsinger J O Valenzuela P Agarwal D Lins and MF Mescher ldquoCutting edge type I IFNs provide a third signal toCD8 T cells to stimulate clonal expansion and differentiationrdquoJournal of Immunology vol 174 no 8 pp 4465ndash4469 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom