Stanley B. Prusiner*
Discovering the Cause of AIDS
Great discoveries in science are infrequent, yet they are the grist that motivates every scientist. This source of motivation is critical because most experiments advance our knowledge little, and even when an experiment "works," the step forward is small. Great discoveries happen within different contexts. Some occur when the scientists are not anticipating the outcome--these are genuine gifts of nature. Others occur when clearly defined questions, usually with "yes" or "no" answers, are posed. And often those posing the query are not the ones making the discovery.
In 1981, the initial description of immunodeficiency in very sexually active, young gay men posed the question of causation (1). That report was followed by an alarming rise in the number of new cases of what became known as acquired immune deficiency syndrome, or AIDS. The immunodeficiency associated with AIDS resulted in the appearance of a rare cancer, Kaposi's sarcoma (KS), and a number of opportunistic infections caused by, for example, Pneumocystis carinii and Candida albicans (2-4).
As the clinical descriptions of AIDS widened in the early 1980s, the dramatic reduction in T lymphocytes and a decrease in the ratio of helper T cells to suppressor T cells became the focus of medical investigators searching for a cause. And as the number of AIDS cases exploded to reach epidemic proportions, so did the hypotheses about its possible causation (5). The appearance of AIDS in distinctly different populations including young gay men, intravenous drug abusers, hemophiliacs, Haitians, infants, and blood transfusion recipients argued for an infectious agent. But what kind of infectious agent would destroy the immune system of so many different groups of people?
With more than 20 million deaths from illnesses resulting from AIDS over the last two decades, learning the cause of this fatal illness was a major discovery, enabling the development of a sensitive blood test and effective drugs. Although I never worked in AIDS research, as a neurologist I examined AIDS patients with nervous system complications, and as a scientist I was engaged in defining the enigmatic infectious agent that caused degeneration of the central nervous system of immunocompetent humans and animals. Most scientists would agree that the discovery of the cause of AIDS by Luc Montagnier and his colleagues at the Pasteur Institute and by Robert Gallo and his colleagues at the U.S. National Institutes of Health ranks as a great scientific discovery. However, I became disturbed by the rancor that seemed to engulf Montagnier and Gallo at each stage in the acquisition of new knowledge about this terrifying disease. Some scientists were all too happy to involve the popular press, whose members were ready to write almost any rubbish that their editors would accept. In the mid-1980s, I had my own troubles with the press but because my work did not impact the lives of hundreds of thousands of people infected with a highly communicable, infectious pathogen, I could retreat by simply refusing to speak to reporters. AIDS researchers did not have that option--too many people were dying of this new scourge!
By both reading the literature and speaking to many scientists, I have developed what I believe is a reasonably accurate view of what Montagnier, Gallo, and their numerous colleagues contributed to our understanding of the cause of AIDS. I have taken care to determine which of my views about priority are supported by the dates of submission and subsequent publication of manuscripts in refereed journals. After all, this is the currency by which scientific discoveries have been and will continue to be judged for the foreseeable future. I did not consider abstracts, presentations at meetings, patent applications, or hearsay. In retrospect, there is no doubt that Montagnier and his colleagues were the first to report the discovery of the virus that we now call human immunodeficiency virus, or HIV (6). Equally important were the contributions of Gallo and his co-workers, who showed that the virus reported by Montagnier was the cause of AIDS (7-10). The work of both Montagnier and Gallo was made possible by the earlier discovery by Gallo's laboratory of the cytokine interleukin-2 (11), which is necessary for the growth of cultured T lymphocytes that support HIV replication. The propagation of large quantities of HIV in cultured T cells enabled the development of a blood test for detecting HIV by Gallo's group (9, 10, 12). Not only did the blood test allow the convincing demonstration that HIV causes AIDS but, equally important, it prevented millions of people from becoming infected with HIV through the transfusion of tainted blood. Certainly, the Montagnier and Gallo laboratories were not alone in these early days of AIDS research (13, 14), but their seminal contributions dominate the field. The contemporaneous and independent isolation of HIV by my colleague Jay Levy at the University of California, San Francisco, demonstrated the presence of HIV in AIDS patients and in healthy carriers (13). (Levy managed not to become embroiled in the controversy and so I will not further address his research here.) Despite all of the evidence, more than a decade would pass before there was universal agreement that HIV is the cause of AIDS (6-17).
Identifying HIV was the critical first step in defining the cause of AIDS, but, as Robert Koch so elegantly pointed out more than a century ago, showing that a particular infectious agent causes a specific disease can be an arduous process. This process is especially complicated when exposure to the agent is followed by an incubation period of months or even years before symptoms begin to appear. Such is the case with AIDS. Compounding the delayed manifestation of AIDS is the immunodeficiency that allows nonpathogenic microbes to become killers and other latent microbes to erupt. Pneumonia caused by P. carinii is rare in immunocompetent people but common in patients with AIDS; yet, P. carinii is not the cause of AIDS. KS, a rare cancer in immunocompetent people but frequently seen in AIDS patients, is caused by human herpes virus 8, also called KS-associated herpes virus (KSHV), which is transmitted sexually but remains latent in immunocompetent people (18, 19). Clearly, neither KS nor KSHV is the cause of AIDS. About 10% of people infected with HIV also carry HTLV-1, the first human retrovirus causing cancer to be identified (9, 10, 13). Thus, the demonstration that HIV causes AIDS was no small task.
I have suggested to Gallo that the scientific process might be well served if he and Montagnier were to write somewhat dispassionate accounts of how the cause of AIDS was discovered. Although Gallo and Montagnier tried to do this (20, 21), the need for each to be called the codiscoverer of the AIDS virus prevented resolution of the scientific dispute. The codiscoverer status had been a political solution devised by U.S. President Ronald Reagan and French Prime Minister Jacques Chirac in their attempt to resolve the dispute over patent rights covering the blood test for HIV.
The three following essays are a collaborative effort by Montagnier and Gallo that describe the different yet complementary paths that each took to discover the cause of AIDS, and both authors concur with each other's description of events.
References and Notes
- M. S. Gottlieb et al., N. Engl. J. Med. 305, 1425 (1981). [Medline]
- M. S. Gottlieb et al., Morbid. Mortal. Wkly. Rep. 30, 250 (1981). [Medline]
- N. J. Ehrenkranz et al., Morbid. Mortal. Wkly. Rep. 31, 365 (1982). [Medline]
- J. M. Karon et al., Morbid. Mortal. Wkly. Rep. Recomm. Rep. 41, 1 (1992). [Medline]
- M. Essex, in AIDS: Papers from Science, 1982-1985, R. Kulstad, Ed. (AAAS, Washington, DC, 1986), pp. 3-7.
- F. Barré-Sinoussi et al., Science 220, 868 (1983). [Medline]
- M. Popovic et al., Science 224, 497 (1984). [Medline]
- R. C. Gallo et al., Science 224, 500 (1984). [Medline]
- J. Schüpbach et al., Science 224, 503 (1984). [Medline]
- M. G. Sarngadharan et al., Science 224, 506 (1984). [Medline]
- D. A. Morgan et al., Science 193, 1007 (1976). [Medline]
- B. Safai et al., Lancet 1, 1438 (1984). [Medline]
- J. A. Levy et al., Science 225, 840 (1984). [Medline]
- D. P. Francis et al., J. Natl. Cancer Inst. 71, 1 (1983). [Medline]
- J. Coffin et al., Science 232, 697 (1986). [Medline]
- B. J. Poiesz et al., Proc. Natl. Acad. Sci. U.S.A. 77, 7415 (1980). [Medline]
- Levy called the virus that he isolated AIDS-associated retrovirus or ARV (13), which turned out to be from the same virus family as Montagnier's LAV and Gallo's HTLV-III, all later renamed HIV (15).
- Y. Chang et al., Science 266, 1865 (1994). [Medline]
- D. Ganem, Cell 91, 157 (1997). [Medline]
- R. C. Gallo, L. Montagnier, Nature 326, 435 (1987). [Medline]
- ------, Sci. Am. 259, 41 (October 1988). [Medline]
- I thank F. E. Cohen, R. Gallo, H. Koprowski, J. Levy, L. Montagnier, and N. Nathanson for helpful comments, and H. Nguyen for help with the manuscript.
The author is at the Institute for Neurodegenerative Diseases, Department of Neurology and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
Issue of 29 Nov 2002,
Copyright © 2002 by The American Association for the Advancement of Science. All rights reserved.