AIDS 20 Years Later...

On June 5, 1981, a one-and-a-half page paper in Morbidity and Mortality Weekly Report (MMWR) noted cases of Pneumocystis carinii pneumonia in five gay men in Los Angeles. The men also suffered from cytomegalovirus (CMV) infections and candidal infections of the mucosa,1 and they used recreational inhalant drugs. The editorial note pointed out: "Pneumocystis pneumonia in the United States is almost exclusively limited to severely immunosuppressed patients." "I was sitting in my office in Building 10,2 going through my usual work and lab data, and I got that first issue ... and I thought this was really odd," recalls Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). He recalls getting a "funny feeling" about it. "I don't like these unresolved things. Was this a bad batch of drugs? I never even imagined at that point that this was a new virus at all." A month later, another MMWR report linked Pneumocystis infection in gay men with a rare cancer: Kaposi's sarcoma (KS).3 This cancer was diagnosed in 20 men in New York City and six in California; six of the 26 had pneumonia. Ten other cases of Pneumocystis pneumonia were diagnosed in California. With that second report, Fauci remembers thinking, "'Whoa; we have a problem; this sounds very much like an underlying infection.'" By late August, a third report4 listed 108 cases--not just in New York and California, but also in Florida, Georgia, and Oklahoma. "The apparent clustering of both Pneumocystis carinii pneumonia and KS among homosexual men suggests a common underlying factor," MMWR's editors wrote. Little did anyone know what that factor was or that it would grease the wheels of the research machine with more researchers and funding than any disease had ever before. This disease syndrome, termed at the time gay-related immunodeficiency disease (GRID), quickly became known as Acquired Immune Deficiency Syndrome, or AIDS. This handful of cases, noticed by a few highly observant clinicians, has ballooned into a worldwide pandemic; more than 36 million people are infected worldwide. In Western countries, it began as a gay man's disease, then appeared in hemophiliacs and other blood and blood product recipients. It quickly became an illness of the marginal, affecting minorities, those living in poverty, and those using intravenous drugs. In the rest of the world, it's been a disease mostly transmitted by IV drug use and heterosexual sex, often in countries where the culture requires women to be compliant. HIV-infected women pass the disease on to their newborns, either in utero, at birth or through breastfeeding. Consequently, its toll on women and children is enormous. Last year, according to the Joint United Nations Programme on HIV/AIDS, 5.3 million new cases were diagnosed; since 1981, 22 million people have died from AIDS--9 million of them women; and, by the end of 1999, 13.2 million HIV-negative children under the age of 15 had lost either both parents or their mothers to AIDS--12.1 million of them in Sub-Saharan Africa.5 "We're witnessing a disease that's different than any that we have dealt with in our lifetimes--in terms of the global epidemic, a disease that rivals what we saw in the bubonic plague centuries ago," says Helene Gayle, outgoing director of the Centers for Disease Control and Prevention (CDC), National Center for HIV, STD, and TB Prevention. For fiscal 2001, the National Institutes of Health has budgeted $2.2 billion for AIDS research alone, the largest budget in the NIH. Furthermore, half of the NIH's international budget is dedicated to HIV/AIDS research. Over the course of 20 years, researchers have developed 17 antiviral drugs; while they have some effect on the virus, they are of short-term use, toxic, and very expensive. No vaccines exist and might not for another 10 to 20 years. This is a rapidly evolving virus that researchers had no knowledge of 20 years ago. Even when identified, it was mistaken for an oncovirus--a retrovirus like the feline leukemia virus (FeLV), which causes cancers in cats that survive the initial infection. In the past 20 years, researchers have learned a lot about HIV. "We probably know more about this virus in the molecular virology and the pathogenesis than any other virus. The more we learn of it, we learn what a formidable virus this is," says Fauci. Robert Gallo, director, University of Maryland Institute of Human Virology in Baltimore, says AIDS reintroduced humility into the research arena. 'Successful' Transmission If the AIDS virus had a brain, it could be credited with selecting one of the most successful transmission modes in humans: via sex and through the blood. While treatable to some extent in Western countries with expensive drugs, AIDS reigns unchecked in developing nations. The lack of medication, political paralysis or hostility, ineffective or nonexistent healthcare infrastructure, sexual repression of women and gays, ignorance, and the stigma of being HIV positive amount to a death sentence. According to UNAIDS, about 95 percent of all new cases are in developing countries. Consider: It currently infects 25.3 million people in Sub-Saharan Africa; 55 percent are women. In addition to the 12.1 million African children who lost both parents or their mothers to AIDS by the end of 1999, another 850,000 children were equally affected in South and Southeast Asia. More than 30 percent of those affected in Asia are women. Conservative estimates are that 600,000 Chinese are HIV-infected. "They reckon that's going to increase tenfold in the next five years ...." states Robin Weiss of University College of London. In the absence of a sterilizing preventative vaccine and effective medications that could eliminate the disease, the only way to prevent transmission is by altering human behavior. "Even if a vaccine were found today," says Karungari (Karusa) Kiragu, research writer and associate, Population Reports, Johns Hopkins University Center for Communication Programs, "it is unlikely that it would be available to all individuals at risk in all countries right away." Thus prevention, she says, remains crucial. Some 15,000 new cases are reported daily. "We need the right partners, we need billions of dollars," says Susie Zeegen, co-founder of the Elizabeth Glaser Pediatric AIDS Foundation. "The need for partners is an important issue. No one organization can do this alone, no one country can do this alone ...; 1,600 children a day in the developing world become infected. That's unacceptable." Looking for the Unknown In 1981, nobody was looking for a retrovirus. Gallo, one of the first to identify it, remembers that in the late 1970s, "people said human retroviruses could not exist." At this point, he recalls, some universities were eliminating their microbiology departments on the premise that serious infectious diseases were "things of the past." After Gallo's lab at the National Cancer Institute discovered that the human T-cell leukemia virus-type 1 (HTLV-1) caused leukemia in humans, that attitude needed revision. But certainly, in 1981, when this discovery was made, no researcher would have guessed that a retrovirus was the culprit--except, perhaps, the CDC's Donald P. Francis, an epidemiologist who had worked with Max Essex at Harvard University on FeLV. Francis, now president of VaxGen in Brisbane, Calif., a company that has the only HIV vaccine in Phase III clinical trials, was right. Bruce Walker, director of Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, saw his first case as an intern. "We went from a time when we didn't even know what was causing this clinical syndrome. For a lot of us, the way we were introduced to this disease was to see a patient who was falling apart." Physicians didn't know what caused this illness or what to do for their patients, he says. Michael Gottlieb, then of the University of California, Los Angeles, School of Medicine, was the first author of the initial MMWR report. He wrote another paper on what was being called "gay pneumonia" that was published in the December 1981 issue of The New England Journal of Medicine6 (NEJM). "It's a new infection," Fauci recalls thinking after reading it. "If it's an infection and it attacks the immune system, I'm an immunologist and an infectious disease specialist." He decided to study this odd disease. Some colleagues were skeptical, he recalls. "They felt something was wrong with me and that I was having a midlife crisis." When Ronald C. Desrosiers of the New England Regional Primate Research Center of Harvard Medical School saw Gottlieb's NEJM article, he realized that there were similarities between what was being reported in humans and what he was seeing in macaque monkeys. "We were having a problem with some of our monkeys, where they clearly had an immunodeficiency problem of some sorts; monkeys [were] dying of CMV infections." After reading the article, "I decided to spend part of my effort to start looking in the monkeys in terms of what might be a cause," remembers Desrosiers. "About one year after the discovery of the human AIDS virus, now called HIV-1 [for human immunodeficiency virus], we discovered a virus in monkeys that is a close relative of HIV called simian immunodeficiency virus [SIV]. And my life hasn't been the same since," Desrosiers wryly notes. Recent evidence points strongly to SIV as the ancestor to HIV.7 On the West Coast Meanwhile, in San Francisco, a group of clinicians, intrigued by what they were reading--and already noticing similar symptoms in their patients--began meeting regularly to discuss this new illness. Marcus Conant, then of University of California, San Francisco, Medical Center; Paul Volberding of San Francisco General Hospital; Arthur Ammann, a pediatrician specializing in congenital immunodeficiencies, then of UCSF; and an oral surgeon and radiation therapist "formed a small group that met once a week in the faculty club," says Ammann, who did the immunological studies. Ammann clearly recalls the first adult AIDS patient he tested: "I remember seeing the T cells and it looked like a patient that was born without an immune system." In the early days of the epidemic, everything was suspect, including CMV and nitrite inhalants called poppers, says Ammann. But something happened that "changed" his career, moving him out of pediatric immunology and into AIDS research and advocacy. "I was referred two patients--children--who had a very [odd] immunodeficiency: low T cells and very high antibody level. That was what we were seeing in acquired immune deficiency syndrome in the adult," he notes. "One infant had received multiple blood transfusions because it was an Rh baby. It was anemic. It had 20-some blood transfusions. The other infant, when we looked into the family situation, the mother was an intravenous drug user." They traced the baby's blood donors with the help of the San Francisco Department of Public Health and the CDC's Harold Jaffe. "We continued to find in children low T cells, high antibody level. We felt it was a unique disease caused by something viral," Ammann recollects. By 1983 and 1984, three labs had isolated the virus: Jay Levy's at UCSF Medical Center, Luc Montagnier's at Institut Pasteur in Paris, and Gallo's at NCI. Breakthroughs and Butting Heads The 20-year history of HIV/AIDS has been characterized by tremendous scientific breakthroughs. "The metaphor I use is a jigsaw puzzle. Sometimes you put one piece in place and suddenly the whole thing becomes clear," remarks virologist Weiss, ruminating to The Scientist on the disease's history. Weiss has been involved in HIV research since 1983. "But there have been some breakthroughs in HIV/AIDS research," he says. "Observing that there was a new disease [was] not a breakthrough but a break. Someone was alert at the CDC. [There were] just a handful of cases. How extraordinary that young adults should be developing Pneumocystis pneumonia and Kaposi's sarcoma. There's something that says, 'That is an immunodeficiency.'" In January 1982, the "CDC [was] showing it was transmissible; suddenly the evidence is there that recipients of blood donations ... hemophiliacs, drug addicts--here was the same disease cropping up in people who probably received contaminated blood. Ergo, it's a transmissible disease," explains Weiss. "The CDC did some really pioneering work ... getting a lot of knowledge before there was a virus. Then there was a big breakthrough in May 1983, less than two years [after the first cases were identified]: the first description or identification of HIV [from] the Institut Pasteur in Paris," says Weiss. Fauci notes, "After a very, very brief period of time from the recognition of the disease, the etiologic agent was discovered. That was paramount." Despite breakthroughs, the history of AIDS has had controversies. One of the initial eruptions was over who identified the virus first--Montagnier's group or Gallo's. The published record shows that the French group described the virus in May 1983.8 The American group described the virus in May 1984.9 The disagreement, which led to lawsuit filings and ended with the U.S. and French presidents signing an accord giving both sides credit, is but one of many controversies--both scientific and policy-related--comprising the epidemic's lore. A more recent one includes South African President Thabo Mbeki's panel to determine if HIV really causes AIDS. The panel reached no conclusion; both sides were absolutely pitted against each other. The results were released in March.10 To add further controversy, Weiss recently wrote in a review of Montagnier's HIV-related memoirs11 that Françoise Barré-Sinoussi, who worked in Montagnier's lab and actually discovered the AIDS retrovirus, is "the Rosalind Franklin of HIV,"11 referring to the X-ray crystallographer who provided the data that led James Watson and Francis Crick to discover the structure of DNA. Despite controversy, the breakthroughs continued. The next was the creation of a blood diagnostic kit, Fauci says. Developed separately by three labs-Weiss's and Montagnier's group in Europe and Gallo's group in the United States, the kit's role was twofold. Explains Fauci, "The test gave us the scope of the epidemic and allowed us to track it, not only where we were at that time in '84 to '85, but it also allowed us to screen the blood supply." Weiss ticks off other early breakthroughs: finding that the CD4 antigen on one of the subsets of T lymphocytes, now called CD4+ cells, functioned as a receptor for HIV [then called lymphadenopathy-associated virus-1 (LAV-1) or human T-cell leukemia virus-III (HTLV-III), depending if one uses Montagnier's identification for the former or Gallo's for the latter;13,14 cloning the viral genome in early 1985; and, in that same year, conducting clinical trials using azidothymidine (AZT), now called zidovudine. Those clinical trials were so impressive, Weiss notes, that the trial was stopped "halfway through because patients on AZT did so much better." What researchers later learned was that the virus becomes resistant to a single drug. It wasn't until 1996, 10 years later, "before we got the right cocktail of drugs that have given people an extra five years of life," says Weiss. He doesn't consider combination antiretroviral therapy (highly active antiretroviral therapy, or HAART) a true scientific breakthrough, "but in terms of mortality, [it] is," Weiss states. "From '86, '87 to the present time, we have a total of 17 antiviral drugs, with more drugs for this disease than any other viral [disease]," notes Fauci. With the advent of HAART, AIDS became a disease that one could live with--at least for some time. Although virologist John Moore of the Joan and Sanford I. Weill Medical College of Cornell University in New York is not one to use the word breakthrough, he says that the pharmaceutical companies deserve credit for developing the antivirals. "The drug industry developed protease inhibitors. [Their] discovery ... of partially effective antivirals is clearly a major breakthrough," he states. Credit should be given to "the community of cellular immunologists--six to 10 really good groups--whose contribution to understanding the immune response to HIV replication has been pretty outstanding," Moore posits. "It has implications both for HIV pathogenesis, for immunology, and for vaccine design." He adds that the companies that developed viral load assays also should be given credit for bringing the science forward. Work with macaques and chimpanzees, especially, has been very important in discovering how HIV works. "We developed a recombinant DNA that was [an] infectious representative that allowed us to discover the contribution of individual genes to pathogenesis," says Harvard's Desrosiers. In 20 years, researchers have learned what should be all they need to know about AIDS. But it isn't. One of the major problems with this virus is its rapid mutation rate within the infected individual. The other problem is that it destroys the immune system's ability to protect against HIV or any other pathogen. These problems are unique to HIV and have ruled out, at least for now, a sterilizing preventative vaccine. For most diseases, creating a vaccine is the first step. For AIDS, it likely will be the last. Myrna Watanabe is a freelance writer in Patterson, New York References 1. M.S. Gottlieb et al., "Pneumocystis pneumonia--Los Angeles," Mortality and Morbidity Weekly Report (MMWR), 30:250-2, 1981. 2. P. Smaglik, "Funding mechanisms affect research culture," The Scientist, 13[20]:24, Oct. 11, 1999. 3. A. Friedman-Kien et al., "Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California," MMWR, 30:305-8, 1981. 4. S.M. Friedman et al., "Follow-up on Kaposi's sarcoma and Pneumocystis pneumonia," MMWR, 30:409-10, 1981. 5. UNAIDS/WHO, "AIDS epidemic update: December 2000," December 2000. 6. M. Gottlieb et al., "Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency," New England Journal of Medicine, 305:1425-31, 1981. 7. B. Korber et al., "Timing the ancestor of the HIV-1 pandemic strain," Science, 288:1789-96, 2000. 8. F. Barré-Sinoussi, et al., "Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)," Science, 220:868-71, 1983. 9. R.C. Gallo et al., "Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS," Science, 224:500-3, 1984. 10. See www.polity.org.za/govdocs/reports/aids/aidspanel.htm. 11. L. Montagnier, Virus: The co-discoverer of HIV tracks its rampage and charts the future, New York: W.W. Norton, 1999. 12. R.A. Weiss, "Of viruses and men," Nature, 405:277-8, , 2000. 13. D. Klatzmann et al., "T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV," Nature, 312:767-8, 1985. 14. A.G. Dalgleish et al., "The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus," Nature, 312:763-7, 1985. Resources The history of the early years of the epidemic through 1988 is chronicled in the late Randy Shilts' book, And the Band Played On, Penguin Books, New York, 1988. Robin Weiss recently reviewed the history of the virus and the current state of knowledge about its evolution and molecular biology in Nature. (R.A. Weiss, "Gulliver's travels in HIVland," Nature, 410:963-967, April 19, 2001.) The Centers for Disease Control and Prevention: www.cdc.gov The National Institutes of Health: www.nih.gov The International AIDS Vaccine Initiative: www.iavi.org The Gay Men's Health Crisis: www.gmhc.org UNAIDS: www.unaids.org The Elizabeth Glaser Pediatric AIDS Foundation: www.pedaids.org

AIDS 20 Years Later...

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