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HIV SPECIAL

The pandemic of HIV infection, the causeof AIDS, is clearly the defining medical

and public health issue of our generation andranks among the greatest infectious diseasescourges in history1. Since the world firstbecame aware of AIDS in the summer of 1981(refs. 2,3), the disease has spread in successivewaves in various regions around the globe. By2003, HIV had infected a cumulative total ofmore than 60 million people, over a third ofwhom subsequently died4. Unfortunately, thecatastrophic potential of the AIDS pandemichas not yet been fully realized. HIV and AIDScontinue to exact an enormous toll through-out the world, notably in sub-Saharan Africa,and their incidence is accelerating in somecountries and regions, including China, Indiaand parts of eastern Europe and central Asia4.

Commensurate with the magnitude of theHIV and AIDS problem has been the extraor-dinary scientific effort to delineate the etiology,molecular virology, natural history, epidemiol-ogy and pathogenesis of disease caused by HIV(reviewed in refs. 5–8). These areas have pavedthe way for the development of effective thera-pies and tools of prevention that have providedenormous benefits to individuals and commu-nities in resource-rich countries and increas-ingly also in resource-poor countries.

As we look back on the 20 years since theidentification in 1983 of HIV as the etiologicalagent of AIDS9,10, it is appropriate to reflect on some of the many accomplish-ments in AIDS science, as well as the numerous challenges that remain. Thousands

of investigators in diverse disciplines havecontributed to an effort that has resulted in anextraordinary, but still incomplete, mosaic ofunderstanding with regard to HIV and AIDS.The collective output of the HIV and AIDSresearch community has been prodigious:more than 125,000 papers related to HIV andAIDS are catalogued in the PubMed databaseof the National Library of Medicine.

Although it would be impossible to describeall of the important scientific contributions inHIV and AIDS research within the context of abrief commentary, I have attempted to high-light in broad strokes some of the main areasof accomplishment in the fight against HIVand AIDS without attempting to be all-inclu-sive. Other authors in this focus will discussthese and additional topics in greater detail.

A new diseaseIn the summer of 1981, clinicians in New Yorkand California observed among young, previ-ously healthy, homosexual men an unusualclustering of cases of rare diseases, notablyKaposi sarcoma and opportunistic infectionssuch as Pneumocystis carinii pneumonia, aswell as cases of unexplained, persistent lym-phadenopathy2,3. It soon became evident thatthese individuals had a common immunologi-cal deficit in cell-mediated immunity, resultingpredominantly from a significant diminutionof circulating CD4+ T cells11,12. Early sugges-tions that AIDS resulted from behavior specificto gay men were largely dismissed when thesyndrome was observed in distinctly differentgroups in the United States.

After several false leads, many investigatorsconcluded that the clustering of AIDS casesand their occurrence in diverse risk groupscould be explained only if AIDS were caused byan infectious microorganism transmitted by

intimate contact, for example through sexualactivity or blood13. As with many emerginginfectious diseases, the initial and most power-ful tool to illuminate the etiology of the diseasewas classic epidemiology. Initial observationsregarding the immunopathogenesis of AIDS,together with a growing understanding ofhuman and animal retroviruses, suggested thatthe disease might have a retroviral etiology9,10.Two retroviruses, human T-lymphotrophicvirus (HTLV)-I and HTLV-II, which had beenrecently recognized at that time, were the onlyviruses known to preferentially infect CD4+ Tcells. The transmission pattern of HTLV wassimilar to that seen among individuals withAIDS; in addition, HTLV-I and related retro-viruses were known to cause varying degrees ofimmune deficiency in humans and animals14.Thus, the search for a new retrovirus wasundertaken in earnest.

In 1983, experimental data indicating anassociation between a retrovirus and AIDSwere published by a research team in Franceled by Luc Montagnier15. In 1984, the Frenchgroup and researchers at the US NationalInstitutes of Health, led by Robert C. Gallo,published seminal papers that established,with virological and epidemiological evi-dence, that the virus now known as HIV wasthe cause of AIDS9,10. The virus was also iso-lated independently by Jay Levy in Californiafrom both individuals affected with AIDS andasymptomatic individuals from groups athigh risk for AIDS16.

As is very often the case in science, the iden-tification of HIV drew heavily on many previous advances, in particular the discovery in the 1970s of the reverse transcrip-tase enzyme used in the replication cycle ofretroviruses17 and the cytokine interleukin-2,which is required for the robust growth of cul-

HIV and AIDS: 20 years of scienceAnthony S Fauci

From the identification of HIV as the agent that causes AIDS, to the development of effective antiretroviral drugs,the scientific achievements in HIV research in the past 20 years have been formidable. Some of the other importantareas of accomplishment include the development of blood tests for HIV and increased knowledge of the molecularvirology, epidemiology and pathogenesis of this virus.

National Institute of Allergy and Infectious

Diseases, National Institutes of Health, Department

of Health and Human Services, Bethesda,

Maryland 20892-2520, USA.

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tured T cells essential to the propagation oflarge quantities of HIV in the laboratory18.

Molecular virology and epidemiologyThe identification of HIV led to intense activ-ity in the field of molecular virology that con-

tinues to the present time. Three structural andsix regulatory genes, which together encode atleast 15 viral proteins, were identified and theirrelationship to the complex mechanisms ofHIV replication soon unfolded7. These find-ings were crucial to an understanding of thereplication cycle of HIV and its relationship to the pathogenic mechanisms of HIV disease.In addition, they provided an avenue to iden-tify important targets for the development ofeffective antiretroviral drugs.

The study of the molecular virology ofHIV also opened the door to the study of themolecular epidemiology of HIV19. The sci-ence of molecular epidemiology was essentialin defining the evolving heterogeneity of HIVthroughout the world, including the presenceof circulating recombinant forms of thevirus20 and the origin of HIV in the humanspecies. With regard to the latter, the zoonoticnature of HIV was established by the closephylogenetic relationship between HIV-2,first identified in West African individuals in1986 (ref. 21), and the simian immunodefi-ciency virus in sooty mangabeys. In 1999, itwas shown that HIV-1 had probably origi-nated from the Pan troglodytes troglodytesspecies of chimpanzees, in which the viruscoevolved over centuries22. Because chim-panzees are killed for food in parts of sub-Saharan Africa, the species jump probablyoccurred by accident.

A blood test for HIVThe next critical advance after the identifica-tion of HIV was the development of a sensi-tive and specific test for antibodies to HIVthat could be used for diagnosing individuals(with confirmation by immunoblot analysis)and for large-scale screening23. This funda-mental scientific advance had immediate andprofound implications for public health.With an ELISA to detect antibodies to HIV,the blood supplies in the United States andother developed countries were screened forHIV and rendered extremely safe by 1985(ref. 24), thereby preventing millions ofpotential transfusion-related infections. HIVantibody tests have subsequently been usedin numerous epidemiological and naturalhistory studies to clarify the global scope andevolution of the epidemic25. Only with theavailability of this simple screening was thereal and potential scope of the AIDS pan-demic fully appreciated.

Before the ELISA for HIV, clinicians weregenerally seeing individuals who were in thelate stages of disease and had a lifeexpectancy measured in months26. The avail-ability of the blood test allowed investigatorsto readily identify asymptomatic individuals

infected with HIV, to describe more accu-rately the true clinical course of HIV disease,and to follow the natural history of the dis-ease prospectively in individuals for whom atime of seroconversion could be determined.

HIV pathogenesisThe pathogenesis of HIV disease, from avirological and immunological standpoint,has been studied intensively and defined pro-gressively over the past 20 years6,8. The path-ogenic mechanisms of HIV disease areextremely complex and multifactorial27

(Fig. 1). Even before HIV was identified, itwas recognized that an apparent paradoxexisted whereby the immune system wasaberrantly activated at the same time that theindividual was experiencing immune defi-ciency5. This was later shown to be due to acombination of the aberrant secretion of var-ious cytokines, many of which could upregu-late virus expression, and the intensive cellsignaling induced by the viral envelope28.Depletion of CD4+ T cells was recognized asa hallmark of disease early on11,12, evenbefore the classic demonstration in 1984 thatthe CD4 molecule was the primary receptorfor the virus on a subset of T cells and mono-cytes29,30. In addition, much evidence sug-gested that other factors were necessary forHIV fusion and entry, but these putative‘coreceptors’ remained elusive for severalyears31.

In the mid-1990s, a number of diverseareas of investigation elucidated the roles ofthe chemokine receptors CXCR4 and CCR5in the efficient binding and entry of two dif-ferent strains of HIV-1 called X4 and R5,respectively6,31. Indeed, RANTES, MIP-1αand MIP-1β, the ligands for CCR5, wereshown to potently inhibit the binding ofvirus to its target cell. This recognition thatHIV could use different coreceptors alsohelped to explain the occurrence of syncytial(CXCR4-using) and nonsyncytial (CCR5-using) variants of HIV6. The importance ofthe CCR5 coreceptor in the pathogenesis ofHIV infection was proven by the finding thatcells from individuals homozygous for adeletion of 32 base pairs in the CCR5 genecould not be infected in vitro with R5 virusesand that such individuals, who compriseabout 1% of white populations, areextremely resistant to HIV infection evenwhen repetitively exposed to virus32.

Studies of lymphoid tissue in individualsinfected with HIV revealed the disseminatednature of HIV infection and the fact thatlymphoid tissue is indeed the chief target andreservoir of HIV infection33,34. In addition, itbecame clear that HIV continually replicates

Primary infection

Massive viremia

Wide disseminationto lymphoid organs

HIV-specificimmune

responseTrapping of virus and establishment of

chronic, persistent infection

Establishmentof infection in

lymphoid tissue

Immune activation mediated bycytokines and HIV envelope–

mediated aberrant cell signaling

Acceleratedvirus replication

Partialimmunologicalcontrol of virus

replication

RapidCD4+ T cell

turnover

Destruction ofimmune system

CD44+

LymphLymphLymphenodee

Figure 1 Pathogenic events in untreated HIV-mediated disease. HIV (pink) enters the bodyand binds to Langerhans or dendritic cells(orange), which carry the virus to CD4+ T cells.Infected CD4+ T cells home to lymphoid tissue,where the infection is established. Virusreplication accelerates, and massive viremialeads to the wide dissemination of virusthroughout the body’s lymphoid tissue. An HIV-specific immune response occurs and virusis trapped on the follicular dendritic cells ofgerminal centers in the lymphoid tissue. At thispoint, chronic, persistent infection is establisheddespite an immunological response to the virus.Immune activation is an important driver of HIVreplication and is mediated by the secretion ofvarious cytokines and by aberrant cell signalingcaused by interaction of the viral envelope withcellular receptors. Because there is usually onlypartial immunological control of virus replication,continual and accelerated production of virusensues. This is associated with a rapid turnoverof CD4+ T cells. Ultimately, lymphocytedepletion occurs, along with destruction of thearchitecture of lymphoid tissue. Adapted withpermission from ref. 6.

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at varying degrees in lymphoid tissue despitethe fact that the individual might appear tobe clinically well. Although the clinical coursevaried widely among individuals, the inex-orably progressive nature of disease in mostindividuals became clear.

An important advance in HIV research hasbeen the development of highly sensitivetechniques for the precise quantification ofsmall amounts of nucleic acids35. The meas-urement of serum or plasma levels of HIVRNA is now an essential component of themonitoring of individuals with HIV infec-tion and, together with CD4+ T cell counts,guides therapeutic decisions36. Assays such asRT-PCR and the bDNA technique fordirectly detecting HIV RNA have helped toclarify the direct relationship betweenamounts of virus and rates of disease pro-gression, rates of viral turnover, the relation-ship between immune system activation andviral replication, and responsiveness to ther-apy6.

The ability to measure plasma viremia pre-cisely led to the classic viral dynamics studiesof Ho and Shaw in 1995, which characterizedthe enormous turnover of virus in HIV dis-ease and the delicate balance bet-ween virus production and T cell dynam-ics37,38. These studies led to a cascade ofinsights into HIV pathogenesis, among theman appreciation of the direct relationshipbetween virus replication and disease pro-gression and the association of a given viralset point in an untreated individual with theprognosis for disease progression39. The lat-ter observation has been essential in the

design of therapeutic strategies and hasguided clinicians in decisions regarding theinitiation and modification of therapeuticregimens36.

The finding of latent reservoirs of HIV,particularly in the resting subset of CD4+ Tcells, has had a sobering effect on hopes oferadicating HIV in individuals whose viralload is rendered ‘undetectable’ by antiretrovi-ral therapy40. Indeed, simple but definingstudies have shown that even in individualsin whom plasmaviremia is driven byantiretroviral ther-apy to levels of lessthan 50 copies ofRNA per ml (‘unde-tectable’) for up to 3years, the viral reser-voir persists and thevirus rebounds fromthis reservoir withinweeks of discontinu-ing therapy41.

Studies of theimmune response toHIV have been bothproductive and frus-trating. Clearly, indi-viduals in whomHIV infection hasbeen established ca-nnot eliminate thevirus from theirbodies40,41. Despitethis consistent ob-servation, individu-

als infected with HIV also show several ele-ments of HIV-specific immunity. Neutral-izing antibodies, potent HIV-specific CD8+

cytotoxic T cell responses and HIV-specificCD4+ T cells are present in many individualsinfected with HIV at various stages of dis-ease6. Unfortunately, CD8+ cytotoxic T cellsselect for escape mutants, and the most effec-tive neutralizing antibodies are directed atcryptic epitopes against which it is difficult toinduce antibodies. Although CD4+ T cellscapable of undergoing lymphocyte blasttransformation to HIV antigens are morelikely to be seen in individuals in the earlystages of disease, the induction of suchresponses has minimal, if any, effect on dis-ease progression6.

Thus, the initial hope that the identifica-tion of HIV-specific elements of the immunesystem in HIV-infected individuals wouldlead to better therapies and vaccines has beenreplaced by the realization that we have yet toidentify a clear correlate of protective immu-nity against HIV infection42. Understandingthe correlates of immune protection andtheir potential role in vaccine developmentremains one of the greatest challenges in HIVand AIDS research.

Therapy for HIV infectionSecond to the identification of HIV as thecausative agent for AIDS, the most impress-ive scientific advances have occurred in thedevelopment of effective antiretroviral drugsfor treating individuals infected with HIV.

Cellular DNA

Reversetranscriptase

Fusion/entryinhibitors

Reverseranscriptasetran

nhibitorsinh

Integraseinhibitors

Protein synthesis,processing

and assembly

Coreceptor

Fusion

gp120

CD4 molecule

HIVBudding

MatureHIV virion

Integratedproviral DNDNA

Unintegratedlinear DNA

Genomic RNA

Genomic RNA

mRNAProteaseeinhibitorrs

Figure 2 The replication cycle of HIV and targets for antiretroviral therapy.

Table 1 Antiretroviral drugs licensed by the US FDA

Drug Approval date

Retrovir (zidovudine, AZT) March 1987

Videx (didanosine, ddl) October 1991

Hivid (zalcitabine, ddC) June 1992

Zerit (stavudine, d4T) June 1994

Epivir (lamivudine, 3TC) November 1995

Invirase (saquinavir-HGC) December 1995

Norvir (ritonavir) March 1996

Crixivan (indinavir) March 1996

Viramune (nevirapine) June 1996

Viracept (nelfinavir) March 1997

Rescriptor (delavirdine) April 1997

Combivir (AZT and 3TC) September 1997

Fortovase (saquinavir-SGC) November 1997

Sustiva (efavirenz) September 1998

Ziagen (abacavir) December 1998

Agenerase (amprenavir) April 1999

Kaletra (lopinavir and ritonavir) September 2000

Trizivir (AZT + 3TC + abacavir) November 2000

Viread (tenofovir) October 2001

Fuzeon (enfuvirtide, T-20) March 2003

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The spectrum of drug discovery for HIV cen-ters on an appreciation of vulnerable targetsin the replication cycle of the virus (Fig. 2).The first effective drug against HIV was thereverse transcriptase inhibitor azidovudine(zidovudine), or AZT43. It was identified by ascreening process using large numbers ofcompounds that had been already producedfor other purposes. AZT was originally devel-oped as an anticancer drug but did not proveeffective in that capacity. It was licensedinstead as the first antiretroviral drug in1987.

Subsequently, more sophisticated sciencein the form of targeted drug design has beenthe rule as drugs have been developed to tar-get specific vulnerable points in the virusreplication cycle, providing a cogent exampleof the importance of the basic researchendeavors in viral biology and the transla-tional approaches in drug development44.The prototype of this approach was theexpression, purification and crystallization ofthe HIV protease enzyme to facilitate the tail-ored design of protease inhibitors a class ofantiretroviral drug that was first approved bythe US Food and Drug Administration(FDA) in 1995 (ref. 45).

The newest class of drug, fusion inhibitors,represents another example of successful tar-geted drug development led by basic sciencediscovery44. These compounds block thefusion of the viral envelope to the cell mem-brane, and became available with the FDAapproval of enfuvirtide (Fuzeon) in 2003(ref. 46). New and improved drugs in all threeclasses (reverse transcriptase inhibitors, pro-tease inhibitors, and fusion and entryinhibitors) are being actively pursued alongwith drugs against alternative targets such asthe viral integrase44. Currently, there are 20FDA-approved drugs or combinations ofdrugs for HIV (Table 1). The availability ofthese therapeutics and their use in combina-tions of three or more drugs have trans-formed the treatment of individuals infectedwith HIV such that morbidity and mortalityowing to HIV disease have sharply declinedin developed nations where such drugs arereadily available25.

HIV vaccinologyThe progression of HIV disease in the settingof vigorous anti-HIV responses remains acentral paradox in the pathogenesis of HIVinfection6,8. Elements of both the humoraland cell-mediated immune responses againstHIV have been implicated in the partial con-trol of viral replication. Even after 20 years ofHIV and AIDS science, however, our lack ofunderstanding of the correlates of protective

immunity in HIV infection continues tohamper the rational development of HIVvaccines47. With 14,000 individuals world-wide becoming infected with HIV every day4,a vaccine that prevents HIV infection or atleast slows the progression of disease in indi-viduals who become infected is badly needed.

Despite the lack of a clear understandingof the correlates of protective immunity inHIV infection and other formidable obsta-cles, significant progress toward an HIV vac-cine has been made47. At the time of writing,numerous promising HIV vaccine candidatesare in various stages of preclinical and clinic-al development. But it is still not clear at thispoint how successful, if at all, we will be inthe development of a vaccine that truly pro-tects against HIV infection. Candidate vac-cines in nonhuman primate models generallyhave not been able to protect against infec-tion, but they have shown protection (at leastfor a time) against disease progression in pri-mates that become infected despite havingbeen vaccinated47. The superinfection ofalready-infected individuals whose currentvirus had been under excellent immunologi-cal control is a troubling observation48.Clearly, the development of a safe and effect-ive vaccine for HIV is one of the mostformidable challenges for research in infec-tious diseases.

ConclusionThe scientific accomplishments in the field ofHIV research over the past 20 years reflect anextraordinary odyssey of discovery. Indeed,these accomplishments represent a model ofwhat can be accomplished when the world’sscientific community is galvanized in a com-mon goal of pitting its best minds and sub-stantial resources against a historic publichealth challenge. This Nature Medicine spe-cial issue will take up in detail these and othercrucial accomplishments in the scientificresponse to HIV and AIDS.

Unfortunately, the HIV pandemic stillrages throughout the world, particularly inresource-poor countries such as those in sub-Saharan Africa, the Caribbean and parts ofAsia. This fact should energize the scientificand public health communities to continuethe quest for scientific discovery and, simul-taneously, to ensure that the fruits of scien-tific discovery are adequately applied to thosemost in need.

ACKNOWLEDGMENTSI thank G. Folkers for help with preparing themanuscript and H.C. Lane for critically reading themanuscript.

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