The Triumph of Retrovirology (1982–1984)
Gallo's Family of Viruses
Writing in 1988, Robert Gallo, the NIH scientist who would share credit for discovery of what was to become known as the "human immunodeficiency virus," reflected back on the scientific effort to understand AIDS. Gallo concluded that progress had been made possible by "two general earlier developments": "first , by major advances that took place in basic sciences, particularly in immunology
… and molecular biology …; and second , by the opening of the whole field of human retrovirology that, oddly enough, occurred only a few years before the AIDS epidemic. …" To this Gallo added, "There is no doubt in my mind that if AIDS came upon us full force in the 1960s or even in the early 1970s, we would still be wandering in the dark regarding most of what we know today."
Gallo's "odd" fact can be put in different terms: At the moment when people began to suspect that AIDS might be caused by an infectious agent, there existed a small group of prominent scientist working in a very specialized area who were inclined to imagine that a "retrovirus" might be the cause, who were motivated to pursue that speculation, and who were well equipped to do so. Only in the 1960s had researchers discovered that the genetic material of certain viruses consists of RNA (ribonucleic acid) rather than DNA (deoxyribonucleic acid, often called the "blueprint of life"). Normally, viruses infect cells and turn them into virus factories, causing the cells to produce new viruses according to the specifications of the rival DNA. The virus's DNA is copied into RNA, which is then used to manufacture viral proteins; once the new viruses are assembled, they are ejected and go off to infect other cells. When viruses were found that consisted of RNA rather than DNA, they presented a puzzle to scientists, because it was unclear how the viruses could replicate. In 1970, however, in work that would win them the Nobel Prize, researchers David Baltimore at the Massachusetts Institute of Technology and Howard Temin at the University of Wisconsin independently discovered that these RNA viruses contained an enzyme, which they termed "reverse transcriptase," that copied the viral RNA into DNA. This DNA then served as the blueprint for the manufacture of new viruses. So while in normal viruses the sequence was "DNA to RNA to new viruses," in these unusual viruses there was an extra step: "RNA to DNA to RNA to new viruses." To describe the transcription from RNA to DNA and back again, virologists coined the term "retrovirus."
During the "War on Cancer" in the 1970s, researchers such as Gallo at the NIH's National Cancer Institute (NCI) investigated links between animal retroviruses and various forms of cancer. However, until the late 1970s, no retroviruses were known to cause disease in humans. At that time, both Gallo and a group of Japanese researchers claimed credit for the discovery of one believed to cause adult T-cell leukemia, a rare form of cancer found mostly in Japanese fishing villages. Gallo named the retrovirus the human T-cell leukemia virus,
or HTLV. This work earned him the Lasker Prize, the highest award in biomedicine short of the Nobel Prize. He found another virus in the same family in 1982, which he claimed caused a different type of leukemia; in consequence, the two viruses became known as HTLV-I and HTLV-II.
As Gallo described it in retrospect, when he first heard about the new syndrome in gay men in 1981, he had no reason to think it might be linked to a retrovirus and indeed had little interest in the issue. Or as Joan Fujimura has suggested more generally, scientists construct and pursue "do-able problems": they do not venture off in any direction at random, but rather structure their work by finding effective ways of integrating and coordinating the relationship between the experimental procedures at hand, the organization of their laboratories, and the social worlds through which they move. Given that the initial hypotheses focused on homosexual lifestyle risks, many virologists simply saw no particular reason to be interested.
By Gallo's account, his curiosity was piqued only in 1982, when James Curran of the CDC briefed NIH researchers about the epidemic, expressing to them his own belief that the syndrome was caused by an infectious agent, and stressing that one hallmark of the syndrome was the helper T-cell deficiency. This was enough for Gallo to hypothesize that the epidemic might be caused by HTLV or by a retrovirus of the HTLV family—by a close relative, that is, of the two viruses whose discovery had already brought him considerable acclaim within the world of virology. After all, HTLV specifically infected helper T cells; moreover, HTLV was known to be transmitted in blood and semen, which seemed also to be plausible transmission routes of the putative agent in AIDS. Finally, there was some precedent for a retroviral role in a condition like AIDS, since a feline retrovirus was linked to immune deficiency in cats. Gallo became convinced that AIDS was an HTLV-linked disease. Only some years later would he do an about-face and make an intriguing confession: "That hypothesis, as it turned out, was wrong. Nonetheless, it was fruitful, because it stimulated the search that led to the correct solution."
Gallo had little patience for alternative hypotheses that were common at the time. The medical tendency to, as he put it, "round up the usual suspects"—CMV, Epstein-Barr virus, and the like—seemed to him unlikely to provide an explanation for what was, after all, a new epidemic. Nor was he impressed by the popular hypothesis of immune overload. Interestingly, he objected not just on empirical grounds—that
immune overload seemed unlikely to account for manifestations in all the risk groups—but also on the basis of his understanding of causality in disease processes: "Whereas some complex diseases … are believed to involve different steps and sometimes different factors, most human disease (even some cancers) can be thought of as involving a primary causal factor. Certainly this has been the case for most past epidemic disease for which we in time did learn the cuase."
Committed in general to what Dubos called the "doctrine of specific etiology," Gallo dedicated his laboratory to an investigation of his hypothesis: that AIDS was caused by the virus he was already working with and had invested in, HTLV. Within weeks of embarking on this search, Gallo's assistants found the leukemia virus in the T cells of two U.S. gay men, a Haitian woman who died of AIDS in France, and a Frenchman who had received a blood transfusion. Gallo sent two papers describing the findings to Science magazine, the preeminent general science publication in the United States. His colleague, Myron ("Max") Essex at the Harvard School of Public Health, sent along a third paper also reporting signs of HTLV infection in AIDS patients.
The French Virus
Meanwhile, across the Atlantic, a similar search for a retroviral cause of AIDS was proceeding according to different premises. In Paris, a group of physicians had been meeting informally to discuss the epidemic, and one of them, an immunologist named Jacques Leibowitch, who was familiar with Gallo's work on HTLV, had become convinced that a retrovirus was the cause. Skeptical of arguments about poppers and promiscuity, Leibowitch specifically hoped to demonstrate "that the cause of AIDS was not homosexually related." But neither Leibowitch nor any of his colleagues knew how to look for a retrovirus, so they set out to enlist the support of Luc Montagnier, chief of viral oncology at the famous Pasteur Institute, a private, nonprofit research institution founded by Louis Pasteur in 1887.
The physicians' group had a hunch that if a virus was causing the depletion of T cells, then there might be higher levels of virus present in people who were at an earlier stage of illness, before most of their T cells had been killed off. So they sent Montagnier samples of lymph tissue from a gay male patient with "lymphadenopathy syndrome"—a
condition of chronically swollen lymph glands, increasingly prevalent among gay men and believed by many to be a precursor to AIDS. Montagnier's research team extracted T cells from the tissue and put them in an incubator with nutrients, hoping to grow a virus. When tests showed the presence of reverse transcriptase, the enzyme that is the distinctive marker of retroviruses, they knew they had found something. The reverse transcriptase activity rose and then fell—a sign that the virus was killing its host cells—but by adding fresh cells from new sources, the French researchers were able to maintain the culture. With the aid of electron microscopy, the Pasteur group also succeeded in photographing viral particles.
When Montagnier contacted Gallo in early 1982 and informed him of his findings, Gallo encouraged him to submit his paper to Science , so that Gallo's, Essex's, and Montagnier's papers could all appear together. Since Science allows its authors to suggest appropriate peer reviewers, Gallo told Montagnier he would be happy to review the Pasteur Institute;s findings for the magazine. In his comments to Science , Gallo urged rapid publication, stressing the importance of Montagnier's work. But in addition, as reported John Crewdson has described in a highly critical exposé of Gallo's work, Gallo offered to write the abstract, which Montagnier had neglected to include. Gallo's abstract identified the French virus as a "C-type retrovirus," similar to Gallo's HTLV. Gallo had effectively enlisted the Pasteur researchers behind his own HTLV.
The papers appeared in Science in May 1983, where, as Crewdson noted, they "made a considerable splash." But few people paid much attention to Montagnier's paper, which followed the other three in the pages of Science ; it appeared simply to confirm the findings of the American researchers. As Jay Levy, a virologist at the University of California at San Francisco Medical School (UCSF), who had also embarked on a search for a retroviral causative agent, later recalled, "The write-up in the Science papers sounded like the French virus and the Gallo virus were the same."
But Montagnier and his collaborators suspected otherwise. Their photographs didn't especially resemble HTLV. And when they exposed their virus to HTLV antibodies, they didn't observe any "cross-reaction"—as they should have, if the virus were really a close cousin of HTLV. Most crucially, their virus killed T cells in the test tube. HTLV caused its host cells to multiply wildly—the hallmark of cancer. Of course, the French had no actual proof at this point that the virus
they had found was indeed the cause of AIDS. But they were increasingly convinced that theirs was a previously undiscovered retrovirus, not HTLV or even a member of the same family; and they set out to demonstrate its causal relationship to the epidemic.
By fall 1983, at the virology conference held each September in Cold Springs Harbor, New York, Montagnier could report finding his virus—which he was now calling "LAV," or lymphadenopathy-associated virus—in about 60 percent of patients with lymphadenopathy syndrome and 20 percent of those with AIDS. None of these patients appeared to be infected with HTLV. At the conference, Gallo angrily disputed Montagnier's findings, claiming that the French measurements had to be in error. (Much later, Gallo would write: "I have come increasingly to regret that the tone or spirit of my questioning that day was too aggressive and therefore misunderstood.") What Gallo did not mention to the conference-goers was that, despite his own lab's best efforts, he and his associates had been unsuccessful in finding HTLV in the majority of samples from AIDS patients that they had been studying over the past several months.
An Addition to the Honor Roll?
The events of the subsequent seven months are obscure, and—despite intensive scrutiny by journalists and a half dozen official investigations by various reputable bodies—the facts may never fully be known. What appears beyond dispute is that, shortly after the Cold Springs Harbor conference, Montagnier forwarded to Gallo a sample of LAV for him to study. Then, the following April, reports of Gallo's discovery of a "third variant" of HTLV began to appear in the pages of U.S. newspapers. Just months after insisting that HTLV was the cause of AIDS—while increasingly having trouble finding it in AIDS patients—Gallo presented the world with a new virus, "HTLV-III," which he claimed was a member of the HTLV family. Later, in January 1985, investigators would determine that Gallo's HTLV-III samples had a 99 percent genetic similarity to Montagnier's LAV—that is, the viruses were much too similar to have come from separate sources. The implications were clear: Whether the consequence of accidental contamination of viral cultures—a common problem in virology labs—or of outright theft and misrepresentation, the Pasteur Institute's LAV had found its way into Gallo's cultures. Almost beyond a doubt, Gallo had in fact "discovered" Montagnier's virus.
Yet none of this was known in 1984. Indeed, there was little said about Montagnier on April 23 that year, when Margaret Heckler, President Ronald Reagan's secretary of health and human services, stood before a roomful of reporters. "The probable cause of AIDS has been found," she announced with some fanfare: "a variant of a known human cancer virus, called HTLV-III." Just a few days earlier, Lawrence Altman, the New York Times 's medical reporter, had received a scoop from CDC Director James Mason, who told him that a virus discovered in France, called LAV, was the likely culprit; the Times had run the story on the front page. "There was so little excitement in the scientific community when the French came up with their announcement last May," noted Mason, claiming he did not understand why it had taken so long for the importance of the Pasteur Institute's work to be recognized. But at the press conference on Tuesday, Mason's boss had a different tune to play.
"Today we add another miracle to the long honor roll of American medicine and science," said Heckler. "Those who have said we weren't doing enough," she added, in response to widespread complaints of inactivity on AIDS by the Reagan administration, "have not understood how sound, solid, significant medical research proceeds." As Randy Shilts described it, the researchers on the podium with Heckler "blanched visibly when she proclaimed that … a vaccine would be ready for testing within two years."
Heckler made only brief reference to the Pasteur Institute scientists, describing them as "working in collaboration with the National Cancer Institute"; she indicated her belief that LAV and HTLV-III "will prove to be the same." Nor was mention made of UCSF virologist Jay Levy, who was also close on the heels of a virus linked to AIDS. (He would submit his paper to Science the following month.) Pressed by puzzled reporters, Gallo added: "If it [the virus] turns out to be the same I certainly will say so…." Heckler emphasized the crucial role of the U.S. research, noting that only Gallo had succeeded in reproducing large quantities of the virus, which was necessary for the development of a blood test that could detect viral antibodies. Hours earlier, the U.S. government had filed a patent application for just such a test.
The New York Times , in an editorial printed a few days afterward, was not slow to draw implications from the episode. "In the world of science, as among primitive societies, to be the namer of an object is to own it," the Times noted wryly, pointing to the dispute between
"LAV" and "HTLV-III." Since the blood screening test was not yet in commercial operation and no vaccine had yet been produced, "what you are hearing is not yet a public benefit but a private competition—for fame, prizes, new research funds."
"Strong Evidence of a Causative Involvement"
Certainly one of many unusual aspects of the whole affair was that Heckler's press conference was held before Gallo's findings had even been published in a peer-reviewed forum—normally a serious breach of professional scientific etiquette in itself. Those who wanted more substantial information about Gallo's claims had to wait until May 4, when four articles by Gallo's group appeared in the pages of Science . This too was extraordinary. As Gallo later commented, "Getting one paper in Science is a lot. Getting two is fantastic. Getting three was a record. We had four at one time."
Gallo used these articles to put forward a series of interconnected claims: that he had found a new virus; that he had succeeded in mass-producing it; that the virus was related to HTLV; that antibodies to the virus could be detected in blood; and, most crucially, "that HTLV-III may be the primary cause of AIDS." In the second of the four papers, Gallo and his coauthors focused specifically on the etiological argument. After reviewing the evidence in favor of an infectious agent as the cause of the syndrome, Gallo reminded his readers that "we and others have suggested that specific human T-lymphotropic retroviruses (HTLV) cause AIDS." Gallo's wording was also significant: he had redefined HTLV, from "human T-cell leukemia virus" in 1983, to "human T-lymphotropic retroviruses " in 1984. While the original name denoted the relation between a single retrovirus and a specific form of cancer, the new name described a family of viruses more vaguely characterized as "T-lymphotropic," that is, having an affinity for T cells. Gallo had reinvented "HTLV" so as to more plausibly encompass his new virus as a relative of HTLV-I and HTLV-II.
Moving on to HTLV-III, Gallo described detecting the virus in, and isolating it from, "18 of 21 samples from patients with pre-AIDS [the so-called lymphadenopathy syndrome], three of four clinically normal mothers of juvenile AIDS patients, three of eight juvenile AIDS patients, 13 of 43 … adult AIDS patients with Kaposi's sarcoma, and 10 of 21 adult AIDS patients with opportunistic infections." Although
ideally one would expect to find a primary causative agent in every case of a disease, Gallo noted that "the incidence of virus isolation reported here probably underestimates its true incidence since many tissue specimens were not received or handled under what we now recognize as optimal conditions." In contrast with these findings that associated the virus with the expression of AIDS was the striking absence of HTLV-III in cases where AIDS was also absent. Out of 115 clinically normal heterosexual blood donors, not a single one showed signs of the virus. And out of 22 clinically normal gay male donors, only one tested positive for the virus, and that person developed AIDS within six months. These studies, Gallo and his coauthors concluded, "provide strong evidence of a causative involvement of the virus in AIDS."
What in fact had Gallo established? Four years later, in response to challenges about whether the virus had been proven to cause AIDS, Gallo would maintain: "In my opinion all of the sufficient data was available at the time the cause was first announced in the spring of 1984." But this was a difficult position to sustain, at least on the basis of Gallo's published findings. Gallo had shown that, in specific small samples, laboratory signs indicating the presence of his virus were often correlated with the expression of AIDS at what were believed to be two different stages of disease progression ("pre-AIDS" and AIDS). Moreover, there were no such signs of virus in clinically normal people, suggesting that the virus or viruses had some special relationship to AIDS. But just because HTLV-III and LAV were often correlated with the syndrome, did that mean they were causing it? AIDS, after all, was a syndrome whose hallmark was the presence of a range of opportunistic infections; perhaps HTLV-III and LAV were viruses that were contracted by people who already had weakened immune systems. Gallo would have been in a better position to respond to this challenge if he had had more cases like that of the clinically healthy but infected gay man who later developed AIDS. But the other 21 of his 22 "clinically normal homosexual donors" all tested negative for the virus, so there was really no evidence that HTLV-III infection was a precursor to immune system damage. (Three out of 4 of the "clinically normal mothers of juvenile AIDS patients" tested positive for the virus, but these numbers were small, and Gallo did not report that any of the women had subsequently developed AIDS symptoms.)
When asked ten years afterward whether he had been able, at
the time of publication, to rule out the possibility that HTLV-III was an opportunistic infection, Gallo acknowledged that he could not. But "the evidence was overwhelming in my mind," Gallo recalled. "Science is never 100 percent. It's not mathematics. You play not on hunches, but on data that becomes overwhelming in your mind. …" To make a credible claim for "strong evidence of a causative involvement," Gallo was in fact relying heavily on the plausibility of HTLV-III as a pathogenic agent, given what was known about the virus and about AIDS. At least in vitro, HTLV-III killed helper T cells. And the central manifestation of immune system damage in people with AIDS was precisely the low numbers of those same helper T cells. Still, at this point, little was known about the effects of HTLV-III in vivo.
Koch's Postulates and the Proof of Causation
Epidemiologists and biomedical researchers rely on a range of principles to establish causation in disease. However, since the acceptance of different versions and interpretations of these principles of causation has itself become one of the stakes in the controversy over the causation of AIDS, these principles cannot be independently invoked as neutral measures. The most well known causation criteria are called "Koch's postulates," named after Robert Koch, the nineteenth-century German microbiologist. The postulates consist of four steps that are easily stated. First, the causal agent must be found in all cases of the disease. Second, the agent must be isolated from a carrier and grown in pure culture. Third, when the culture is injected into a susceptible laboratory animal, the animal must contract the disease. Finally, the causal agent must then be recovered from the diseased animal.
The precise relevance of Koch's postulates to contemporary biomedical research (particularly with regard to viruses, which were unknown at the time of Koch's own work) is in dispute, and this dispute has been magnified as a result of recent debates about the causation of AIDS. Many have proposed that researchers nowadays must work with "modern" or revised versions of the postulates, and have argued that Koch himself did not intend them to be followed rigidly. Nevertheless, Koch's postulates remain a well-known reference point for considering questions of etiology in scientific medicine.
For instance, Richard Krause, the director of the National Institute of Allergy and Infectious Diseases of the NIH, gave a conference talk in the summer of 1983 on "Koch's Postulates and the Search for the AIDS Agent," noting that "technical difficulties" often "impede the fulfillment" of all of Koch's postulates, but concluding: "If we abide by the scientific guidance of Koch's postulates, we are sure to discover the cause of AIDS." Similarly, Lawrence Altman focused squarely on Koch's postulates in an article, published later in 1984, on "How AIDS Researchers Strive for Virus Proof." Altman presented Koch's postulates as an important medical tradition that researchers have looked to for a century, but he noted that doctors are sometimes forced to rely on immunological or other experimental evidence when Koch's postulates cannot fully be satisfied. With less equivocation, James D'Eramo wrote in the New York Native soon after the Heckler press conference: "The definitive classical proof that a virus or bacterium causes disease rests on causing the disease in animals by injecting them with the putative agent. AIDS has yet to occur in a laboratory animal." Dr. Nathan Fain, the medical writer for the national, West Coast-based gay newsmagazine the Advocate, made roughly the same claim in May when he explained why "work must continue to prove beyond all doubt that the candidate virus does cause AIDS."
Clearly, if Koch's postulates are the benchmark, then Gallo's May 1984 articles in Science by no means established HTLV-III as the cause of AIDS. But since the criteria for proving causation have been contested, it may be useful to assess the credibility of Gallo's claims-making by looking at a relatively weak version of the causation criteria presented in a recent epidemiology textbook. According to Mausner and Kramer, the likelihood that an association is causal can be evaluated by examining several criteria. First, there is the strength of the association, which they describe as the "ratio of disease rates for those with and without the hypothesized causal factor": here Gallo's evidence is compelling but far from perfect, since he was able to isolate the virus only in fewer than half of the samples from people actually diagnosed with AIDS. Second, the "dose-response relationship": does a higher dose of the causal factor result in higher rates of disease expression? Gallo had no data on this point. Third, the consistency of the association across different studies: clearly this was yet to be determined. Finally, is the association a "temporally correct" one, meaning that the cause precedes the expression with a sufficient "induction period" or "latency period"? With the exception of the
one virus-positive, clinically healthy gay man who developed AIDS within six months, Gallo had no relevant data to report.
Given the state of the evidence in early 1984, perhaps a more plausible claim was that of Jay Levy, whose results in isolating what he called "ARV," or AIDS-associated retrovirus, were published in August. Levy found signs of ARV in about half his AIDS patients and in about 20 percent of clinically healthy homosexual men, but in only 4 percent of clinically healthy heterosexuals. Levy recalled agonizing over how to phrase his conclusion: "I called a good friend of mine … who's an editor, and I said, 'How do I do this? I don't want to say it isn't, but I don't want to say it is .'" In the end, Levy's wording was cautious: "Although no conclusion can yet be made concerning their etiologic role in AIDS, their biologic properties and prevalence in AIDS patients certainly suggest that these retroviruses could cause this disease."
But for Gallo, the notion that he had proven the virus to be the cause became something crucial to defend, particularly as his credibility on other claims was challenged. In 1985, the Pasteur Institute sued the U.S. government in a patent dispute over the discovery of the virus, and in 1987 the heads of the two governments, Jacques Chirac and Ronald Reagan, signed an agreement splitting the royalties for the commercial antibody test. Especially after it became apparent that Montagnier's LAV had found its way into Gallo's viral cultures—a point that Gallo would formally concede in 1991—Gallo gradually backed off from claiming any primacy. And although Gallo continued to present the discovery of HTLV-III as a natural outgrowth of HTLV research, he was eventually forced to accept the prevailing view that, from a genetic standpoint, the new virus was not reasonably classifiable as an HTLV virus. In response to the confusing array of acronyms then in use—HTLV-III, LAV, ARV, HTLV-III/LAV, and others—the Human Retrovirus Subcommittee of the International Committee on the Taxonomy of Viruses rebuffed Gallo and agreed on a new, compromise, name in 1986: HIV, human immunodeficiency virus. (Levy and Montagnier signed the agreement; Gallo and his close associate, Max Essex, dissented.)
The Framing of AIDS
The naming of the virus by the Human Retrovirus Subcommittee marked the initial stabilization of "HIV" as a unitary
object of medical knowledge. But even before this point, the illness AIDS had become a relatively stable cultural entity whose social meanings, however fluid and multiple, had at least begun to congeal. Over the course of a few years, AIDS had come to be "framed," or constructed, within the context of strong beliefs and attitudes about sexuality, promiscuity, and homosexuality and through recourse to a wide range of analogies: Was AIDS like cancer? Was it like herpes? Was it like hepatitis B? Was it an HTLV-like illness? AIDS itself had also come to serve as a frame for understanding other events and social behaviors. Perhaps most notably, as sociologist Steven Seidman has argued, "AIDS … provided a pretext to reinsert homosexuality within a symbolic drama of pollution and purity."
These framings, and the associated stigma, had also provided possibilities for gay men to assert claims for "ownership" of the epidemic (however ambivalently), or at least some of the public responses to it. Indeed, the same social networks and institutional linkages that had permitted rapid amplification of a virus also gave rise to the organization of a concerted grassroots response. Lesbians, subject to what Erving Goffman has called a "courtesy stigma," or stigma by association, acted as collaborators with gay men in these efforts, often playing leadership roles. This extraordinary success of gay and lesbian communities in establishing their right to speak about the epidemic would fuel a willingness and capacity to challenge the knowledge-making practices of biomedicine in the coming years.
Biomedical researchers, and in particular virologists, had also staked out claims to "ownership" of AIDS, and had done so through powerful findings concerning a probable causal agent. The credibility of AIDS research would rapidly become linked to the credibility of this particular causal claim: between 1984 and 1986, the retroviral hypothesis would achieve near-hegemonic status among scientists. It would also, by and large, be taken for granted in the communities affected by the epidemic, in the mass media, and among the lay public. The pathways, mechanisms, and consequences of the "black-boxing" of HIV are the topics of the next chapter.