Topic review HIV eradication

HIV cure and eradication

Rationales and Options

Pana Tanjararak, MD

Introduction

• Despite significant reduction in morbidity and mortality following combination antiretroviral therapy (cART) cannot eradicate HIV

• Long lived latently infected cells and residual viral replication

• Anatomical reservoirs – GI tract – Lymphoid tissue – Central nervous system

Sharon R Lewin and Christine Rouzioux. AIDS 2011; 25: 000-000.Infectious diseases unit, The Alfred, Monash University Melbourne, Australia.

Laboratory of virology, Hopital Necker, Universite Paris Descartes, Paris, France.

Why do we need a cure for HIV?

• Full life expectancy not been restored

• In a prospective study of 3,990 HIV-infected in Denmark, – HIV patient reaching the age of 70 was 50%

that of uninfected population controls

• Incidence morbidity also elevated despite successful cART due to complex interactions – Drug toxicity – Persistent inflammation– Risk behaviours

• Financial resource to support life long Rx

Why do we need a cure for HIV?

Functional or sterilizing cure

• 2 potential strategies for cure

• Infectious diseases model– Elimination of all HIV infected cells in all

compartments and sanctuaries and plasma HIV RNA < 1 copy/ml (Sterilizing cure)

• Cancer model– Long term health in the absence of treatment,

with low level viremia < 50 copies/ml. (Functional cure)

Sterilizing cure: Elimination of HIV following BMT

• The recent case report of a German patient with AML – BMT from a donor who carried a 32 base pair

deletion in the CCR5 gene – The only current example of a sterilizing cure

• Stop cART

• HIV RNA remained at <1 copy/ml.

• No HIV-DNA or HIV-RNA were detected– Multiple biopsies of GI tract– Brain biopsy– Analysis of CSF– Bone marrow

• > 45 months post stopping cART and HIV is still not detected

• Reconstitution of circulating and mucosal CD4+ T-cells that did not express CCR5

• Mutant CCR5+ mucosal macrophages were detected early post transplantation in the GI tract but at later timepoints,

• The patient’s PBMC were permissive to CXCR4, patients CD4+ T-cells were not resistant to HIV

• Potential factors leading to the elimination of long lived reservoirs in this patients (Cells that express CCR5)– Specific chemotherapy – Total body irradiation– Low grade graft versus host disease eliminating

the capacity for any residual replication by removing target cells that express CCR5.

• Strategy of using BMT with a CCR5 mutant donor not a realistic cure for HIV given the toxicity of the treatment

• Need comprehensively study to fully understand how and why HIV was eliminated

Functional cure: elite controllers (EC)

• Long term HIV-RNA < 50 copies/ml (absence of Rx)• Role of genetics, virus and immune response in EC• HLA Class 1 genes• Effective cytolytic CD8+T-cell response in blood which

has been associated with enhanced activity of the T-box transcription factor t-bet

• Increased production of IL-21• Strong HIV specific CD4+ and CD8+ T-cell responses

were also identified in mucosal tissue from EC• The innate immune system may also be important with

enhanced activity of myeloid dendritic cells• Effective immune response, perhaps via vaccination,

may be one strategy to achieve a functional cure.

• Some elite controllers do not bear the protective alleles HLA B27/ HLA B57

• Mechanisms other than enhanced T-cell immunity have also been explored

• No evidence currently that activated CD4+ T-cells from EC patients resistant to HIV

• In contrast to Pts on cART with HIV RNA <50 copies/ml, there is evolution in HIV RNA sequences in EC in approximately 7% of EC, CD4+ T-cells decline over time

• EC potentially be the best candidates to test strategies sterilizing cure – Low total number of infected cells – Robust HIV-specific immune responses

Blood or tissue?

• The highest concentration of HIV DNA and cell associated US HIV RNA in patients on cART is found in tissues such as lymphoid or GI tract tissue

• HIV DNA and RNA in the GI tract 10 times that in blood in patients on cART

• In a recent study of anatomical reservoirs in RT-SHIV infected macaques on cART

• The largest pool of infected cells (measured by cell associated HIV-DNA and US RNA)– Lymphoid tissue (including spleen and lymph node) – GI tract

• Minimal residual infected cells were detected in the– CNS – Reproductive tract

Blood or tissue?

• It is likely that factors that maintain and or allow for the establishment of latency may differ in blood and tissues

• Therefore it is critical that for new interventions aimed at eradication, if at all possible, quantification of latently and productively infected cells, should include tissue as well as blood

Current and future strategies: advantages, disadvantages

• Treatment intensification– There have been a number of studies that have

looked at the effect of treatment intensification on residual virus, in patients receiving cART.

– These studies have included the addition of agents to an already suppressive regimen

• Enfuvirtide• Protease inhibitors (ritonavir boosted atazanavir or lopinavir) • Raltegravir

– No study demonstrated decline in low-level viremia IUPM or cell associated HIV DNA

• In addition, 2 small non randomised studies showed no significant decline in residual virus infection in the GI tract following intensification with raltegravir or in the CSF following intensification with maraviroc, lopinavir/ritonavir or enfurvitide

• A recent small, nonrandomised intensification study with maraviroc, a CCR5 antagonist– This is the only intervention to date that has

shown a decrease in the number of latently infected cells (measured by IUPM)

– The mechanism for how maraviroc may be working is unclear

• Early treatment – Cell associated HIV DNA and HIV US RNA,

decreases to a significantly lower level– In a recent longitudinal study

• Patients who initiated cART during very early acute infection and stayed on cART for a prolonged period

• 5/32 (16%) patients following cessation of cART, HIV RNA was maintained at < 50 copies/ml for a median of 77 months off cART

• Early treatment– Contrast to many other reports of viral

rebound in nearly all patients following cessation of cART, even when initiated during acute infection

– Role of very early treatment requires further investigation

• Elimination of latently infected T-cells via induction of virus production

• Induce virus production from latently infected cells productively infected cell die– JAK-STAT pathway– Activation of NF-kB: prostratin– Enhance histone acetylation: histone deacetylase

inhibitors (HDACi)– Inhibit DNA methylation: methylation inhibitors– Combination strategies

• JAK-STAT pathway– IL-7 is a cytokine that can effectively induce

productive infection from latently infected resting CD4+T-cells

– IL-7 is currently undergoing clinical trials (ERAMUNE)

• Activation of NF-kB: prostratin– Promote T-cell activation and HIV

transcription in vitro– The large diversity of latently infected T-cell

subsets may differ in their capacity to proliferate, and/or uptake of these drugs

– Not yet been assessed for safety and toxicity

• Enhance histone acetylation: histone deacetylase inhibitors (HDACi)– latency can be reversed– Viral production can be activated by

promoting histone acetylation– Modify gene expression by changing the

acetylation state of histones, leading to enhanced transcription from multiple genes including from the HIV LTR

• Enhance histone acetylation: histone deacetylase inhibitors (HDACi)– In cancer cells, HDACi induce cell death and cell cycle arrest of

rapidly dividing malignant cells and many HDACi are now in advanced clinical development for the treatment of different cancers

– HDACi treatment of latently infected cells lines• valproic acid • MCT1• MCT3 • Oxamflatin• Vorinostat• panobinostat

– Preferential apoptosis in cells producing virus

• Enhance histone acetylation: histone deacetylase inhibitors (HDACi)– A theoretical risk of HDACi is that they will

induce activation of other retroviruses and/or DNA viruses

• including CMV, HBV and JC viruses

• Inhibit DNA methylation: methylation inhibitors– The methylation inhibitor 5-aza-deoxycytadine

(decitabine) is a nucleoside analogue that promotes DNA cytosine methylation

– Rx of MDS– Similar effect to HDACi in promoting HIV

transcription in vitro (only in a subset of latently infected resting CD4+T-cells)

• Inhibit DNA methylation: methylation inhibitors– Potency was greatest when used in

combination with other drugs such as prostratin and an HDACi

– Histone methyltransferase inhibitors (HMTis)• Also active in latently infected cells

• Combination strategies– a combination of strategies, for example SAHA +

prostratin appears to have greatest potency in promoting HIV transcription, at least in vitro

– Most of the studies that evaluate a combination approach have been performed in latently infected T-cell and monocytic cells lines and it is currently unknown whether this approach will also enhance potency in latently infected primary T-cells

Boosting immunity to HIV: therapeutic vaccination

• Induction of T-cell immunity via vaccination may potentially generate a functional cure

• Therapeutic vaccination in patients receiving cART has not been successful

• In one of these studies– treatment interruption resulted in a

significantly shorter time to viral rebound following therapeutic vaccination compared with placebo

• The animals who received the polyICLC vaccine had significantly elevated titres of neutralising antibodies compared to the control groups suggesting that the generation of neutralising antibodies may be important in preventing viral rebound following cessation of cART

Making cells resistant to HIV

• Mimic HIV eradication in the HIV-infected German patient include gene therapy to reduce expression of CCR5

• Successfully perform in mice through the introduction of a zinc finger nuclease into hematopoietic progenitor cells, which effectively disrupts the gene coding for CCR5 in all daughter cells

• Reduction in the expression of CCR5 in a subset of transplanted cells.

• Following HIV infection of these mice, there was a selective advantage for the CCR5-/- cells which subsequently increased, HIV RNA remained low and CD4+ T-cells were preserved in both blood and tissue

• A recent phase 2 study – Demonstrated that infusion of autologous T-

cells transduced with a zinc finger nuclease was safe in a small study of 6 HIV-infected patients on cART

• An alternative approach is to use RNA-based gene therapy to reduce CCR5 expression, as well as specifically inhibit HIV replication

• The investigators demonstrated that this procedure was safe and that the transduced genes persisted in a subset of cells for 24 months

• Although wide spread use of these therapies is many years away, these results are encouraging for the possible development of a gene therapy based treatment strategy that may achieve a functional cure.

Moving toward clinical trials to test for eradication

• Animal models– Trialed in macaques to determine efficacy– Limited number of antiretroviral agents that are active

to control of SIV RNA to <50 copies/ml for a prolonged period of time.

– High cost– Finally most detailed analyses of factors that modify

HIV transcription have been performed in vitro models of latent HIV infection in human cells and it is unclear whether this can be translated to SIV infection.

• Recent work has however demonstrated that infection of rhesus macaques with SIVmac239 that contains the HIV- 1 RT from clone HXBc2 (RT-SHIV) treated with tenofovir, emtricitabine and efavirenz appears to be a very promising model of suppressive cART

• These animals had detectable but low level viremia of 2-58 copies/ml consistent with suppressive cART in humans

• Blood-liver-thymus (BLT) mouse that can be efficiently infected with R5 HIV – HIV RNA declines in response to ART

Clinical trial

• First– Measuring the reservoir is complex – Require large volumes of cells – Invasive – No assays have yet been standardised across

multiple laboratories– Unknown what assay will best predict the

likelihood of viral rebound following cessation of cART

Clinical trial

• Second– Most studies small, non-randomised studies– Need for larger randomised studies

• Third– Careful consideration of the risk benefit

• Finally– There remains a need for more

multidisciplinary studies including the use of mathematical models to study the dynamics of reservoirs taking in account half-life of the subsets of infected cells and their homeostatic proliferation

Clinical trial

Conclusion

• There are multiple barriers to the eradication of HIV infection and despite some recent significant advances in vitro models of latency

• Better animal models

• Identification of several compounds that can reverse latency in vitro

• There is still a need for more research

HIV Cure and Eradication

Chemokine Receptor 5 Knockout Strategies Using Zinc-finger Nuclease

Rongpong Plongla, MD

•Typically 110 nm in diameter•containing two single strands of RNA

•Viral genome 10 kb

Marvin S Reitz Jr., and Robert C Gallo. InMandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. 2009

The Life Cycle of Human Immunodeficiency Virus Type 1

Marvin S Reitz Jr and Robert C Gallo. InMandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. 2009

Joan stephenson. JAMA. 2002;287(13):1635-1637.

Mechanism of HIV entry

Jose’ A Este’, Amalio Telenti. Lancet 2007; 370: 81–88 Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autnoma deBarcelona, Badalona, Spain (J A Este PhD)

and Institute of Microbiology, University Hospital Centre, University of Lausanne, Lausanne, Switzerland (A Telenti MD)

• Glycoprotein 120, the viral-envelope protein, binds to the CD4 molecule on susceptible cells, but cell entry requires the presence of a coreceptor.

• The coreceptor for macrophage-tropic non–syncytia-forming strains is CCR5, a surface chemokine receptor.

– Such viruses have recently been renamed R5 viruses to reflect their coreceptor requirement

– whereas T-cell–tropic, syncytia-inducing viruses, which require CXCR4 for entry, are termed X4 viruses.

• Langerhans' cells, tissue dendritic cells-- the earliest target of the virus, express CCR5 but may not express CXCR4, the coreceptor required for the entry of X4 viral isolates.

James O. Kahn, M.D., and Bruce D. Walker, M.D. N Engl J Med 1998; 339:33-39

From the AIDS Program, San Francisco General Hospital and the University of California, San Francisco (J.O.K.), and Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (B.D.W.)

• This may explain why R5 viruses are the predominant strains transmitted during acute HIV-1 infection. • This receptor pattern also explains why persons who are homozygous for a 32-bp deletion in CCR5 (CCR5Δ32) are relatively resistant to infection with the usual R5 strains, although rare cases of transmission of X4 viruses have recently been reported in such persons.

• Irrespective of the route of transmission, R5 viruses are preferentially transmitted over X4 viruses, and acute infection is almost exclusively associated with R5 strains.– The basis of this preferential selection is unclear, but many

barriers to infection by X4 viruses have been proposed.– R5 viruses also predominate during most of the chronic stage of

the disease. • X4 variants eventually emerge in 40–60% of HIV-1-positive

individuals. – X4 variants have been associated with expanded cell tropism,

an increased virus replication rate, faster disease progression, and the onset of AIDS.

– Whether the emergence of X4 phenotype is a cause or consequence of HIV disease progression remains controversial.

Jose’ A Este’, Amalio Telenti. Lancet 2007; 370: 81–88 Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autnoma deBarcelona, Badalona, Spain (J A Este PhD)

Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.

R5 Infection R5 + X4 Infection

Time Since Seroconversion

Current assays’ X4 detection limit

Weeks Years

HIV Tropism and Disease Progression

R5 virus

X4 virus

Jose’ A Este’, Amalio Telenti. Lancet 2007; 370: 81–88 Retrovirology LaboratoryIrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autnoma deBarcelona, Badalona, Spain (J A Este PhD)

R5 HIV-1 strains are commonlytransmitted and persist during the course of infection but might evolve to dual tropic (D) or mixed (M) virus populations, and to X4 phenotype at late stages of disease. Of treatment-naive individuals •12–19% have D/M viral populations•< 1% are infected with X4 viruses. Of treatment-experienced•22–48% have D/M viral populations2–4% are infected with X4 viruses.

CCR5 wild type CCR5 32

2 normal copies 1 copy of 32 2 copies of 32wt/wt wt/32 32/32

Standard diseaseprogression

Delayed disease progression

“Resistant” to HIV infection

Normal Heterozygous Homozygous

CCR5 Wild Type and CCR5 32

Liu R, et al. Cell. 1996;86:367-367. Samson M, et al. Nature. 1996;382:722-725. Dean M, et al. Science. 1996;273:1856-1862. Huang Y, et al. Nat Med.1996;2:1240-1243. Michael NL, et al. Nat Med. 1997;3:1160-1162. Eugen-Olsen J, et al. AIDS. 1997;11:305-310.

Patients Homozygous or Heterozygous for CCR5 32

• Homozygous– ~ 1% of white population[1]

– Lack CCR5 molecules on CD4+ cell surface[2,3]

• Resistant to R5 viruses: natural resistance to HIV acquisition• Susceptible to infection with X4 virus

– Relatively normal immune function• Heterozygous

– 10% to 15% of white population[1]

– Fewer CCR5 molecules on CD4+ cell surface[4]

– Normal immune function[2]

1. McNicholl JM, et al. Emerg Infect Dis. 1997;3:261-271. 2. Liu R, et al. Cell. 1996;86:367-367. 3. Samson M, et al. Nature. 1996;382:722-725. 4. Wu L, et al. J Exp Med. 1997;185:1681-1691.

The first phase involves the rapid decay of the cells that produce the vast majority of the plasma virus. • These appear to be activated CD4+ T cells. • In the productively infected state, these cells have a very short half-life, surviving only about 1 day before dying from viral cytopathic effects or host cytolytic effector mechanisms. a second, slower phase of decay.• This reflects the turnover of a minor population of virus producing cells. • These may be infected macrophages, which are more resistant to the cytopathic effects of infection or CD4+ T cells that are in a state of partial activation. •These cells turn over with a half-life of about 2 weeks.

14 day

J Allergy Clin Immunol 2008; 122: 22-8

• Latently infected resting memory CD4+ T cells are the best characterized latent reservoir for HIV-1.• Less than 1 cell per 1,000,000 resting CD4+ T cells from patients on HAART harbor latent HIV-1 provirus.• Sequence of latent proviruses does not evolve, which suggests no ongoing viral replication.• Discontinuation of HAART allows viral relapse from latent reservoir.• Patients successfully treated with HAART for longer than 10 years exhibit no appreciable decrease in the size of the latent reservoir.• The persistence of latently infected memory CD4+ T lymphocytes precludes their elimination by HAART alonefor the lifetime of the patient.• Other drug-insensitive reservoirs, including brain, macrophages, and hematopoietic stem cells, may also exist.• Latency is likely established and maintained by numerous blocks at multiple steps in the HIV-1 replicative pathway, which potentially complicates eradication strategies.

Douglas D. Richman.* David M. Margolis, Martin Delaney, Warner C. Greene, Daria Hazuda, Roger J. Pomerantz.

Science 6 March 2009: Vol. 323 no. 5919 pp. 1304-1307 . University of California San Diego

Can We Do Better Than HAART?

The Berlin Patients

• A 40-year-old white man with newly diagnosed acute myeloid leukemia (FAB M4 subtype, with normal cytogenetic features)

• HIV-1 infection > 10 years– TDF/FTC/EFV for the previous 4 year– CD4 T-cell count was 415 per cubic millimeter, and HIV-1 RNA

was not detectable – Web position specific scoring matrix (WebPSSM), and

geno2pheno bioinformatic software: not found X4 variant – The ultradeep sequencinganalysis revealed a proportion of 2.9%

for the X4 and dual-tropic variants combined.

N Engl J Med 2009;360:692-8.

allogeneic stem-cell transplantation with CD34+ peripheral-blood stem cells from an HLA-identical donor who had been screened for

homozygosity for the CCR5 delta32 allele.• no active, replicating HIV could be detected 20

months after HAART had been discontinued• HIV-1 virus could not be detected in peripheral

blood, bone marrow, or rectal mucosa, as assessed with RNA and proviral DNA PCR assays.

N Engl J Med 2009;360:692-8.

• The loss of anti-HIV, virus-specific, interferon- γ–producing T-cells during follow-up suggests that HIV antigen stimulation was not present after transplantation.

N Engl J Med 2009;360:692-8.

D14 D625

Immunosuppressive treatment has been stopped 38 months

• demonstrate successful CD4 T-cell reconstitution at the systemic level as well as in the largest immunologic organ after CCR5 32/32 SCT

Blood 2011; 117: 2791-99.effector memory cells (EM), central memory cells (CM), recent thymic emigrants (RTE), and central naïve cells (CN)

• and in addition provide evidence for the reduction in the size of the potential HIV reservoir over time : Brain, Liver, Colon

• Although the recovered CD4 T cells are susceptible to infection with X4 HIV, the patient remains without any evidence of HIV infection for more than 3.5 years after discontinuation of ART.

• Immunoblot analysis revealed a continuing decline of HIV specific antibodies thereafter demonstrating the process of serodeconversion:– HIV core-directed antibodies (p17, p24) disappeared completely– the serum level of antibodies against the HIV envelope (gp41,

gp120) further decreased.

Blood 2011; 117: 2791-99.

Paula Cannon, CROI2011

CCR5 knockout strategies

• However, the risks associated with allogeneic transplantation and the impracticality of obtaining sufficient numbers of matched CCR5Δ32 donors mean that broader application of this approach will require methods for generating autologous CCR5−/− cells.

• Various gene therapy approaches to block CCR5 expression are being evaluated CCR5-specific – Ribozymes, siRNAs, Intrabodies– The targeted cell populations include both mature T

cells and CD34+ HSPCs. – Loss of CCR5 in HSPCs appears to have no adverse

effects on hematopoiesis

Holt N, etal. Nat Biotechnol. 2010 Aug;28(8):839-47.

An alternative approach: the use of engineered ZFNs to permanently disrupt the CCR5 open

reading frame.

• A significant advantage of this approach is that permanent gene disruption can result from only transient ZFN expression.

• disruption of CCR5 in HSPCs is likely to provide a more durable anti-viral effect and to give rise to CCR5−/− cells in both the lymphoid and myeloid compartments that HIV-1 infects

Holt N, etal. Nat Biotechnol. 2010 Aug;28(8):839-47.

ZFNs: designer restriction enzymes

• Contain 2 linked domain– DNA-binding zinc finger protein

• Artificial array of zinc finger peptides confer sequence-specific DNA-binding properties

• a string of ‘zinc-finger motifs’, each a stretch of around 30 amino acids, stabilized by a zinc ion, that binds to a particular three base

• DNA sequence.– DNA-cleaving domain

• Endonuclease domain of type 1 restriction enzyme FokI

• Not specific• must dimerize to achieve efficient DNA

cleavage

Paula Cannon and Carl June. Current Opinion in HIV and AIDS 2011; 6: 74-79.Molecular Microbiology & Immunology, University ofSouthern California Keck School of Medicine, Los Angeles, California and Department of Pathology andLaboratory

Medicine, University of PennsylvaniaSchool of Medicine, Philadelphia, Pennsylvania, USA

Flavobacterium okeanokoites

Fyodor D. Urnov1, Edward J. Rebar1, Michael C. Holmes1, H. Steve Zhang1 & Philip D. GregoryNature Reviews Genetics 11, 636-646 (September 2010)

Pre-clinical testing using humanized mice

• optimized the delivery of CCR5- specific ZFNs to human CD34+ HSPCs (nucleofection, viral vectors)• transplanted the modified cells into non-obese diabetic/severe combined immunodeficient/ interleukin-

2rγnull (NOD/SCID/IL2rγnull; NSG) mice, which support both human hematopoiesis and HIV-1 infection. • Infected the mice with a CCR5-tropic strain of HIV-1

Nat Biotechnol. 2010 Aug;28(8):839-47.

Clinical Trials

SB-728

Nat Biotech 200825% CCR5 modification

About 50% of the human population has antibodies !

6%, 3%, 1%, 2% and 2% at 14 days

Fever, Fatigue

Treatment interruption

• “This isn’t for mass production or fully ready for prime time,” cautioned Scott Hammer, an AIDS researcher at Columbia University and a vice chair of the conference.

• “This is early work that takes molecular biology into the clinic. Like everything else in science and HIV, it’s an early and important finding, but we shouldn’t be raising the flag to say we’ve solved the problem yet.”

BMJ 2011; 342:d1373

many questions remain unanswered:

• What will happen long-term with the newly engrafted CD4 cells? Will they provide a survival or comorbidity benefit in these patients? (Note: Patients in this study will be followed for life.)

• Will this approach help control HIV replication in patients who stop antiretrovirals after long-term HIV suppression?

• How can we ethically ask patients to enroll in studies that require a structured treatment interruption?

• Will institutional review boards be willing to approve these kinds of studies in the future?

• Do people do better with more than one infusion? What is the best number of cells to ensure optimum immunological response?

• Will this approach help control HIV replication in treatment-naive patients who have a detectable viral load and who are not taking HIV antiretrovirals? Will these cells still have a survival advantage when challenged with untreated HIV?

• Will these gene-modified cells have a survival and activity advantage against HIV across the board? Will HIV viral load be controlled well enough for people to stop using antiretrovirals -- or, as stated in the question above, allow them to avoid antiretrovirals entirely?

• What will the cost of this procedure be?

• What happens to those with pre-exposure to the adenovirus vector who cannot respond to this type of zinc finger nuclease delivery method?

Thank You

Topic review HIV eradication

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