A History of AIDS: Looking Back to See Ahead
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S94 Warner C. Greene Eur. J. Immunol. 2007. 37: S94–102 Breakthroughs in Immunology A history of AIDS: Looking back to see ahead Warner C. Greene Gladstone Institute of Virology and Immunology, University of California, Received 5/7/05 San Francisco, CA, USA Revised 22/8/07 Accepted 4/9/07 [DOI 10.1002/eji.200737441] Since breaking onto the scene 26 years ago, HIV has proven an indefatigable foe. Over 60 million people have been infected with this retrovirus, and 25 million have already died of AIDS. HIV infection is hitting the hardest in the developing world [1]. Tragically, Key words: 1600 babies continue to acquire HIV every day from their infected mothers. Over 12 AIDS Á Drug design/ million children have also been orphaned by AIDS, and this number will likely double by discovery Á Global 2010. With these sobering statistics as a backdrop, this feature traces the history of the pandemic Á HIV devastating HIV/AIDS pandemic and offers a view for what the future may hold. Á Infectious diseases Unfolding of a pandemic The appearance of AIDS in Haiti fueled speculation that the disease had originated there. Although not compell- ing, these theories stoked the fear and prejudice AIDS was first recognized in the summer of 1981 surrounding the disease. (Table 1). Young gay men began falling ill and dying of By late 1982, epidemiologic evidence indicated that opportunistic infections their immune systems should AIDS was an infectious disease transferred by bodily have fended off [2]. Those afflicted became emaciated fluids and by exposure to contaminated blood or blood and often developed dark purple lesions on their arms products [3]. Without a test for AIDS, blood banks had and faces due to a relatively rare and aggressive form of difficulty safeguarding the blood supply, and most cancer called Kaposi's sarcoma. In cities such as New refused to screen donors for homosexuality. Surrogate York and San Francisco, prematurely “old” young men markers, such as hepatitis B core antigen, proved became a common sight. Physicians were baffled, and imperfect at best. Thus, the blood supply remained fear spread through the gay community with every new unsafe for years, and many people were transfused with case of what was termed the “gay plague.” Almost contaminated blood. One such person was Elizabeth without fail, patients experienced a rapid downhill Glaser, who in turn transmitted the disease to her course and death as their doctors vainly treated one unborn child, Ariel. Their deaths triggered an outcry for opportunistic infection after another. more research and ultimately led to the formation of the Because the acquired immunodeficiency syndrome Elizabeth Glaser Pediatric AIDS Foundation. Approxi- (AIDS), a name recommended by the Center for Disease mately 15 000 hemophiliacs in the US became infected Control (CDC) in September 1982, was most common in with HIV as a result of transfusion with contaminated gay men and intravenous drug users, early theories blood products between 1981 and 1984. Similarly, about its cause focused on “lifestyle” issues, including intravenous drug users were at high risk due to exchange “immune overload” from multiple infections, use of amyl of blood during needle sharing. The first needle or butyl nitrate “poppers,” a reaction to semen, infection exchange program was set up in Amsterdam in 1984; by an unidentified fungus, and multiple sex partners. such programs would rapidly spread in Europe but not within the US. Correspondence: Dr. Warner C. Greene, Gladstone Institute of The first clues to the true cause of AIDS stemmed Virology and Immunology, 1650 Owens Street, San Francisco, from careful immunological investigations. One con- CA 94158, USA sistent manifestation was a rapid decrease in levels of Fax: +1-415-355-0153 e-mail: [email protected] circulating CD4 T cells. Once those levels fell below 3 Abbreviations: CDC: Center for Disease Control Á roughly 200 cells/mm , patients became vulnerable to HAART: highly active antiretroviral therapy myriad opportunistic infections and various malignan- f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2007. 37: S94–102 Breakthrough S95 cies. Strikingly, this same subset of T cells is the target of Understanding what makes HIV tick the first-described human pathogenic retrovirus, HTLV- I, isolated in 1980 by Robert Gallo and colleagues [4]. In 1985, Ryan White, a 13-year-old boy with hemophilia However, rather than inducing CD4 T-cell depletion, was banned from school because he was infected with HTLV-I transforms these CD4 T cells, resulting clinically HIV. Rock Hudson died of AIDS – the first such celebrity in adult T-cell leukemia [5]. Early on, serum from to be stricken, and President Ronald Reagan finally HTLV-I-infected patients appeared to weakly stain cells mentioned the word AIDS during a press conference. from AIDS patients, suggesting that this new immuno- More positively, Princess Diana personally visited AIDS deficiency might be caused by a retrovirus closely patients and shook hands without gloves, visibly related to HTLV-I. While this connection was ultimately demonstrating to the world that the virus is not casually proven false, in retrospect, scientists were on the right transmitted. track in suspecting a retrovirus. On the scientific front, the sequence of the HIV genome was reported [15–17]. Compared to many other pathogens, its 9-kb RNA genome was rather simple: nine Searching for the cause of AIDS genes encoding 15 proteins. However, HIV would prove anything but a simple virus. First, like a “smart weapon,” In 1983, the CDC documented heterosexual transmis- it seeks out and destroys the very cells that orchestrate sion of AIDS, a finding that began to change the the immune response to viral infection, CD4 T lympho- perception of AIDS as solely a disease in gays [6]. cytes. Secondly, because of the error-prone nature of its Reports of two “different” epidemics emerged from reverse transcriptase and the recombination that occurs Europe, one involving homosexuals but a second between viruses simultaneously infecting the same cell, curiously in immigrants from Central Africa with no HIV evolves at “hyper-light speed” [18, 19]. A swarm of known risk factors. Subsequently, it would become clear billions of different forms of HIV are present simulta- that heterosexual transmission accounts for more than neously in infected patients – a fact that would confound 80% of new infections worldwide [1] and that sub- future treatments and vaccine development. Saharan Africa bears the highest infection rates. In 1983, Three enzymes were quickly identified within HIV – the world also gained its first glimpse of the true cause of reverse transcriptase, protease, and integrase, each a AIDS. Using tissue from a “pre-AIDS” patient with acute prime therapeutic target (Fig. 1). Indeed, in 1987, AZT, a lymphadenopathy, Luc Montagnier and colleagues at cancer drug that also inhibits the reverse transcriptase, the Pasteur Institute detected a new human retrovirus became the first approved anti-HIV drug. Unfortunately, [7]. By electron microscopy, it appeared to be different in what would become a familiar refrain, its therapeutic from HTLV-I. However, with only a single difficult-to- effectiveness proved short-lived. Drug-resistant variants passage viral isolate in hand, it remained unclear of HIV rapidly emerged when single antiviral agents whether this retrovirus was truly the cause of AIDS. A were deployed. causal link between this virus and AIDS was forged by A better understanding of the very first interactions Robert Gallo and his colleagues at the National Institutes of the virus with its target cell pointed the way to new of Health in 1984 [8–10]. Jay Levy and coworkers [11] at classes of therapies. The CD4 transmembrane protein UCSF also independently isolated this new retrovirus. In was identified in late 1984 as one of two receptors May 1986, the International Committee of the Taxon- needed for viral entry [20, 21]. This finding explained omy of Viruses chaired by Harold Varmus recommended why CD4 T cells are specifically killed by HIV. However, that this pathogen with many names be called the 12 years would pass before the chemokine receptors, human immunodeficiency virus (HIV) [12]. CXCR4 and CCR5, were implicated as essential HIV Isolation of HIV enabled the development of the first coreceptors [22–24]. A continuing mystery is why blood test in 1985 [13, 14], a step that offered great hope CCR5-utilizing strains of HIV are almost uniformly to both the scientific and lay communities. Margaret M. transmitted between people, while CXCR4-tropic viruses Heckler, then US Secretary of Health and Human only emerge late in the infection and only in about half Services, predicted in 1984 that a vaccine against HIV of patients, often heralding a more rapid clinical decline. would be available within 2 years. Unfortunately, her Particularly in persons of European descent, a mutated enthusiasm belied a limited understanding of the many version of the CCR5 gene containing a 32-base pair defenses of HIV. Reflecting the scientific tumult swirling deletion was detected that prevents cell-surface express- around HIV, in December 1985, Institute Pasteur filed ion of the receptor; the roughly 1% of individuals suit against the National Cancer Institute claiming a homozygous for this mutation proved highly resistant to share of the royalties from the NCI blood test for AIDS. HIV infection [25]. This “experiment of nature”