NATURE|Vol 453|15 May 2008 OPINION ESSAY 25 years of HIV Reflecting on how far we have come scientifically since isolating HIV in 1983, Anthony S. Fauci urges a renewed commitment to the far greater challenges ahead, especially that of vaccine development.

he HIV/AIDS catastrophe has been one tors from different disciplines began of the defining features of the working on this new disease. Within Tpast quarter of a century. months of the recognition of the first

Although it is short-lived in the cases in the summer of 1981, I shifted (1983) 868–871 220,

scheme of public-health crises, the the direction of my laboratory from pandemic ranks among the most the study of inflammatory diseases SCIENCE devastating microbial scourges to this curious new syndrome. My in human history, one whose full research has been closely intertwined impact has yet to be realized. with HIV and AIDS ever since. For ET AL. Sixty million people have been nearly two years, the cause of AIDS infected with the human immunode- remained elusive; the scientific ficiency virus (HIV); nearly half have community was largely baffled, died, and the toll on families, commu- lacking good leads for developing F. BARRÉ-SINOUSSI, nities and even entire nations has been therapies or even a diagnostic test. profound. Meanwhile, the biomedical Those of us caring for patients research effort directed at HIV/AIDS with AIDS had few tools at our has resulted in some breathtaking disposal. The only treatments we successes. Unlike many other diseases could provide were largely palliative that affect mostly the poor, marginal- and the lifespan of most of our patients was ized and disenfranchised, HIV/AIDS measured in months. Those years were the captured the attention of world leaders, darkest of my professional career. the medical, public-health and activist communities, funding agencies, phi- of the AIDS pandemic. Glimmer of hope lanthropists and many celebrities. This Only in retrospect can we Twenty-five years ago this month came a resulted in an unprecedented scientific identify its different stages. The first glimmer of hope. In 1983, Luc Montagnier’s and public-health response to the disease, began in June 1981, when physicians in New research team in Paris published in Science the and in welcome attention to some of the many York and California reported unusual clusters first paper (pictured) providing evidence link- other problems endemic in those populations of rare diseases in previously healthy gay men, ing a retrovirus to AIDS. The following year, most severely afflicted with HIV/AIDS, such as notably Pneumocystis carinii pneumonia and a further data from Robert Gallo’s group in the malaria, tuberculosis and gender inequality. form of cancer called Kaposi’s sarcoma. When United States provided convincing evidence Much remains to be accomplished in the glo- we in the medical profession read those initial that this retrovirus (later named HIV) was the bal fight against HIV. There cases 27 years ago — and cause of AIDS. That these two outstanding sci- are many more scientific and “HIV/AIDS is treated some of the early entists became embroiled in a controversy — medical hurdles to be cleared predominantly a disease AIDS patients — our pre- largely played out in the media — about who and numerous logistical and vailing emotion was bewil- discovered HIV was an unfortunate distrac- operational obstacles to of the developing derment. tion. As they would later write in The New Eng- making therapies and other world, where access to I had seen other ‘mystery’ land Journal of Medicine: “Many lessons can be interventions available to scientific advances and diseases in my career, such drawn from this early intense period, and most poor countries, where per as the legionnaires’ disease suggest that science requires greater modesty.” capita income is sometimes therapies is difficult.” outbreak of 1976. But AIDS A quarter of a century on, the importance of only a few hundred dollars a was from the beginning collaboration, collegiality and, yes, modesty, year and health-care spending a tiny fraction much more insidious and enigmatic. As cases are ever more apparent, as it becomes clear of that. Reflecting on the era of HIV/AIDS, we began to appear among distinctly different that no single research group or discipline will must learn from our mis-steps, build on our social groups in 1981–82, and as we began to solve the puzzles of HIV/AIDS. successes in treatment and prevention, and understand better the profound and complex After the discovery of HIV, research moved renew our commitment to developing the truly immunodeficiency of our patients, it became at a breathtaking pace. A blood test to diagnose transforming tools that will one day put this clear that we were witnessing the unfolding of patients and to screen the blood supply quickly scourge behind us. something truly novel and frightening. The followed, as did enormous progress in under- severity of AIDS and the signs that it appar- standing the genetics and structure of HIV and Baffling beginnings ently could be spread by a ubiquitous human its disease-causing mechanisms. The rapid People living through historic events often activity — sex — suggested that we were in for clinical testing and licensing in 1987 of the first fail to recognize the significance of what they a difficult time. effective drug against HIV, zidovudine (AZT), experience. Such was the case for me, and The scientific community marshalled its caused great excitement. In retrospect this was many of my colleagues, in the first months resources and talent to fight AIDS; investiga- unfounded, as the molecular characteristics

289 OPINION NATURE|Vol 453|15 May 2008

of HIV, notably its propensity to replicate of the virus, particularly its ability to AP and mutate rapidly, made any single drug integrate into the genome of host cells, unlikely to hold the virus in check. Previous to mutate readily and to conceal that experience with antimicrobials for other part of its outer coat that would induce diseases and the inevitable emergence protective antibodies. of drug-resistant pathogens should have It is now clear that we were naive to made us more cautious about the pros- think there would be a straight path pects for AZT monotherapy. from the discovery and characteriza- HIV quickly developed resistance to tion of HIV to the development of a AZT and the benefits of the drug rapidly vaccine. HIV has proved very different waned. Initial optimism about therapy from those viruses for which we have gave way to sobering reality as the AIDS developed effective immunizations. We pandemic continued to grow in the must solve the mystery of how to prompt United States and elsewhere. Clinicians the human body to produce a protective remained hobbled by a lack of effective immune response that is even better than anti-HIV drug regimes, and many more the one elicited by natural infection. This patients were lost to AIDS. will require a commitment to fundamen- Gradually, the fruits of cutting-edge tal research to address the many questions drug development began to appear. In that remain about HIV and its interactions late 1995, the first of a new class of antiretro- Agent identified: early images captured with its human host. HIV/AIDS science, viral drugs — protease inhibitors — reached by Robert Gallo (top) and Luc Montagnier of the particularly that involving a vaccine, is in some the market. Other new drugs that attacked the retrovirus later named HIV. ways still in its infancy. We must move forward virus in different ways followed, and we soon by fostering creative thinking over many dif- had a greater number of effective drugs for a lifetime. Sadly, because of the ability of HIV ferent disciplines. HIV than for all other viral diseases combined. to hide within cells from both drugs and the In this regard, the pursuit of new research The new therapies used in combination with immune system, such a treatment regime has avenues by established scientists and especially older medicines rapidly improved the progno- proved elusive, although important work in by younger investigators is critical. In addition sis for vast numbers of HIV-infected patients. this area is being pursued. to the disciplines classically associated with The AIDS death rate in the United States fell by This leaves us with the second option: pre- HIV research — virology and immunology more than two-thirds within two years of the venting HIV infection in the first place. We — we must encourage more ‘cross-fertilization’ licensing of the first protease inhibitor. Despite have a proven array of HIV-prevention and with other fields such as genetics, structural certain limitations of the new treatments, nota- harm-reduction strategies: behavioural mod- biology, systems biology and peptide chemistry bly toxicity and drug resistance, they launched ification; condom distribution; antiretroviral as we strive to generate the knowledge needed a new era of optimism. drug regimes to prevent HIV transmission to develop an HIV vaccine. But HIV/AIDS is predominantly a disease of from mother to baby; and the provision of Delivering HIV interventions for the people the developing world, where access to scientific clean needles and syringes to drug users. We it most affects requires political will, a advances and therapies is difficult. Fewer than must now do better at delivering prevention: long-term supply of considerable financial one-third of the people who need antiretroviral less than 20% of those at risk of HIV infection resources, scientific and public-health vision, therapy are currently receiving it, despite heroic are currently receiving such help. and dedication from all sectors of society. efforts on the part of individuals and organiza- Encouragingly, new means of preventing With these ingredients, the trajectory of our tions, and some truly transforming and innova- HIV are emerging. Large randomized and fight against the HIV/AIDS pandemic in tive programmes such as controlled clinical trials the next quarter of a century could move the Global Fund to Fight “The major goal of HIV/AIDS in Africa suggest that from cautious optimism towards triumph. AIDS, Tuberculosis, and research eludes us: the adult male circumci- Absent any of these factors, and history will Malaria and the US Pres- sion, if properly and not judge us kindly. ■ ident’s Emergency Plan development of a safe and hygienically performed Anthony S. Fauci is director of the National for AIDS Relief. Further- effective HIV vaccine.” and accompanied by Institute of Allergy and Infectious Diseases more, it is clear that treat- appropriate counselling (NIAID) at the US National Institutes of Health ment alone will never end the AIDS pandemic. and post-surgical care, can help prevent men in Bethesda, Maryland, and chief of the NIAID New infections far outstrip our ability to treat becoming infected with HIV by heterosexual Laboratory of Immunoregulation. everyone infected with the virus: around three intercourse. Ongoing work to develop micro- people are newly infected for every person put bicidal gels or creams to be applied before sex FURTHER READING Barré-Sinoussi, F. et al. Science 220, 868–871 (1983). on therapy — and current HIV therapy is a life- offers the hope of empowering women to pro- Fauci, A. S. & Lane, H. C. in Harrison’s Principles of Internal long commitment. tect themselves from HIV infection when the Medicine, 17th edition (eds Fauci, A. S. et al.) 1137–1204 use of condoms or the refusal of sexual inter- (McGraw Hill, New York, 2008). More mountains course is not feasible. Fauci, A. S. Science 239, 617–622 (1988). Gallo, R. C. & Montagnier, L. N. Engl. J. Med. 349, 2283–2285 To improve these formidable odds, we have Yet the major goal of HIV/AIDS research (2003). two main options. The first is to cure patients, eludes us: the development of a safe and effec- Joint United Nations Programme on HIV/AIDS (UNAIDS) that is, to purge every vestige of virus from tive HIV vaccine, our best hope for ultimately AIDS Epidemic Update: December 2007 (UNAIDS, Geneva, 2007). their bodies so that a course of treatment could ending the pandemic. The search for a vaccine Levy, J. A. HIV and the Pathogenesis of AIDS (ASM Press, be measured in weeks or months rather than has been made extremely difficult by the nature Washington DC, 2007).

290