Monthly Archives: January 2014

Who Discovered HIV?

The Nobel Committee rewarded Luc Montagnier and Françoise Barré-Sinoussi for the discovery, but passed over Robert Gallo, who did much of the basic research that made the discovery possible.

Our story mainly involves two research groups; Robert Gallo and his colleagues at the U.S. National Institutes of Health, and Luc Montagnier and his colleagues at the Pasteur Institute in Paris. But first, we begin with a few tangential personal recollections, followed by relevant background to provide the setting for our tale.

The herpes simplex viruses and Epstein-Barr virus were the viruses that most excited the interest of my students in the 1970s, almost certainly because of their association with genital infections and infectious mononucleosis (the “kissing disease”), respectively. But, the major interest that these herpesviruses held for my students changed suddenly and dramatically in 1983 with the discovery of HIV as the cause of AIDS. In the more straitlaced early 1980s, excitement over HIV/AIDS was at least in part due to its association with human sexuality in all its forms.

HIV remains a hot topic. Nevertheless, the attention that HIV initially garnered has to some extent diminished as new emerging viruses, such as West Nile Virus, the SARS coronavirus, and the avian and swine influenza viruses arrived to replace the already familiar HIV as the most interesting of viruses. Another development which somewhat diminished concern over HIV is that while a positive HIV diagnosis in the 1980’s was essentially a “death sentence,” the development of new antiretroviral drugs has since turned AIDS into a manageable chronic infection for many HIV-infected individuals. And, in our less prudish times, the association of AIDS with sex may now rouse less interest than it did in earlier times.

The somewhat ephemeral nature of what is trendy in science, as illustrated here by the declining interest in HIV/AIDS, perhaps reflects the short-lived nature of what is hot in contemporary culture in general. This may help to explain my experience of only a few years ago when I began to excitedly recount for my virology class, comprised mostly of microbiology majors, how Robert Gallo and Luke Montagnier vied to be recognized for the discovery of HIV. I was most surprised to realize that not any of my students had ever heard of Gallo and Montagnier. This disquieting experience compels me to tell this story here. It is rich in human, scientific, political and, perhaps now, historic interest, and needs to be told.

Before beginning the story of the discovery per se, it would be good to recount again the extent of human suffering wrought by the AIDS epidemic. It was indeed enormous, especially in its early years when there were no therapies to treat what was then an almost invariably fatal infection. Indeed, the emergence of HIV/AIDS was by some criteria the worst outbreak of an infectious disease in history. Approximately 65 million people in the world were infected by the fall of 2007, and the rate of new infections remains at several million per year. Of these, 50,000 HIV infections still occur annually in the United States, and these disproportionally involve African-Americans and other minorities.

In view of the above, the unearthing of HIV as the cause of AIDS can well be regarded as one of the great discoveries of medical science. First, it led to the development of sensitive tests for HIV infection, which made it possible to asses the effectiveness of world-wide prevention efforts. And, by identifying those who might be infected, the tests significantly slowed the spread of the infection. What’s more, the tests also made the world’s blood supply safe from the virus. Second, and critically, the identification of a retrovirus as the cause of AIDS opened up the use of antiretroviral therapy to treat AIDS patients, thereby dramatically reducing morbidity and death. In fact, current antiretroviral regimens can lower viral levels in some HIV-positive patients to the point where even the risk of transmission is negligible.  And, pre-exposure prophylaxis (PrEP) may soon be available, in the form of a single pill (e.g., Truvada, a combination of the antiretrovirals, tenofovir disoproxil fumarate and emtricitabine). [Nevertheless, bear in mind that even now, with the availability of effective antiretroviral drugs, the virus is still present and ready to multiply if treatment is interrupted. Furthermore, many patients, particularly in the developing world, do not have access to these therapies. And, an HIV vaccine remains problematical. The reasons for the latter are discussed in Virology: Molecular Biology and Pathogenesis.]

Precious little was known about the underlying basis of AIDS before HIV was isolated and confirmed as its cause. Consequently, many wrongheaded hypotheses were put forward to explain the origin of the disease. For example, since AIDS first appeared among cohorts of gay men, some researchers proposed that the disease might be caused by sperm in the male bowel. And, since AIDS is characterized by a severe immunodeficiency, others suggested that it might be caused by excess stress that some individuals placed on their immune systems. Yet some investigators did suggest that AIDS might be caused by a virus. Thus, cytomegalovirus, Epstein-Barr virus, hepatitis B virus, and the herpes simplex viruses were all investigated as the possible cause of AIDS.

Interestingly, very few biomedical scientists thought that AIDS might be caused by an as yet unknown infectious agent (based on the conceit that all infectious agents had already been identified), much less a retrovirus. Indeed, prior to the discovery of HIV, it was generally thought that there are no human retroviruses; a view based on previous failed attempts to find retroviruses in human cancers. In this regard, it had been the hope of many an ambitious retrovirologist to find an oncogenic human retrovirus.

As it was, the two research groups featured here were among the very few that persisted in the search for retroviruses in human cancers. And, it was fortunate that their searches focused on leukemias in one laboratory, and T lymphocyte cultures from breast cancer patients in the other. As a consequence of their ongoing efforts, when the first patients with AIDS were identified in 1981, one of these groups was able to provide the conceptual and technical tools to isolate the AIDS virus, which the other group used to actually isolate the virus.

The stage is now set for Robert Gallo to play a key part in our story. In 1980, just before the first patients with AIDS were recognized, Gallo and his associates discovered the first known human retroviruses. These were two closely related viruses, isolated from patients with an unusual adult T-cell leukemia. Accordingly, Gallo originally named them “human T-cell leukemia virus I and –II” (HTLV-I and –II). These viruses are also known as the human T-lymphotropic virus I and –II. [See below regarding the origin of the second meaning of “L” in the acronym.]

Bearing in mind that all earlier efforts to isolate a human retrovirus were unsuccessful, why was Gallo able to isolate HTLV-I and -II in 1980? Part of the answer is as follows. During the previous 15 years, Gallo had been studying other mammalian leukemogenic retroviruses. To facilitate those studies, Gallo’s group developed methods for growing T lymphocytes in culture for extended periods. This advancement depended on the earlier discovery by Doris Morgan in Gallo’s laboratory of the T-cell growth factor, now known as IL-2.1 Importantly, the ability to grow T lymphocytes in cell culture, which enabled Gallo to grow the HTLVs, would be a critical breakthrough with regard to isolating HIV, since HIV specifically targets CD4 helper T lymphocytes in vivo. Moreover, it would be a key to developing the blood tests that detected the virus.

Other investigators also made significant advances. One of these was the discovery only ten years earlier of reverse transcriptase by Howard Temin and David Baltimore. 2 The availability of reverse transcriptase made it possible to develop highly sensitive PCR-based assays for detecting a retrovirus. These developments, taken together, enabled Gallo’s group to isolate HTLV-I and –II in 1980. And, consequently, when AIDS emerged, tools were already in place to search for a retrovirus as its causative agent.

When AIDS then suddenly appeared on the scene, Gallo saw several clues which hinted to him that its etiologic agent might be a retrovirus similar to the HTLVs.3 First, AIDS is characterized by a severe loss of CD4 CD4 helper T lymphocytes, and HTLV was already known to target T cells. Second, HTLV was known to be transmitted via blood and sexual activity, and from mother to infant; the very modes by which AIDS was proving to be transmitted. Third, a high incidence of AIDS was being reported in Haiti, a region in which HTLV is endemic. Thus, Gallo’s premise was that AIDS is caused by a variant of HTLV. That premise would prove to be incorrect, but Gallo was indeed correct in hypothesizing that it is caused by a retrovirus.

Now we turn to Luc Montagnier, a retrovirus researcher at the Pasteur Institute, who was at the time of the AIDS outbreak investigating the possible involvement of retroviruses in human breast cancers. Toward that end, Montagnier was cultivating T cells from breast cancer patients, and assaying the culture medium for reverse transcriptase activity.

In 1982, influenced by Gallo’s arguments, Montagnier set out to isolate a retrovirus as the possible etiologic agent of AIDS. As Montagnier noted, “At that time there were only a few cases in France, but they attracted the interest of a group of young clinicians and immunologists. They were looking for virologists, especially retro-virologists, as a likely hypothesis was that HTLV – the only human retrovirus known so far, recently described by R. C. Gallo – could be involved.” 4

Before Montagnier began his search for the AIDS agent, a group of French physicians and scientists suggested to him that the best chance to find and isolate it might be at the start of the disease, before the patient’s T cells had severely declined. Their reasoning was that if a virus were found at this early stage of the disease, then it would more likely be its cause, rather than merely a consequence of the immune depression. So, Montagnier and co-workers looked for a retrovirus in a lymph-node biopsy from a patient with persistent lymphadenopathy (swollen lymph glands), an early sign in patients progressing towards AIDS, but with little sign yet of the impending severe immunodeficiency. [In their later joint report, Gallo and Montagnier noted: “The idea that the causative agent of AIDS should be sought in swollen lymph nodes was partly right, since we now know that lymph nodes are the main site where the virus hides during the presymptomatic phase.” 3] Cells from this patient were cultivated in the presence of IL-2, as per Gallo’s earlier finding, as well as anti-interferon antiserum. The latter was an innovation of Montagnier, based on the earlier finding in Paris that interferon repressed the replication of retroviruses in cell culture. Two weeks later, in early January 1983, Montagnier’s research group detected the first evidence of reverse transcriptase activity in the cell culture medium.

Contrary to expectations, the new retrovirus detected in Montagnier’s laboratory was not an HTLV. This was initially shown by the fact that it did not react with anti-HTLV antibodies that were provided by Gallo. Moreover, when Montagnier’s isolate was viewed by electron microscopy, its morphology was clearly different from that of an HTLV. The difference between these viruses was further confirmed by sequence analysis. However, and crucially important, antibodies against Montagnier’s new virus were later found to be present in serum from most AIDS patients, and the virus was shown to have a tropism for CD4 T cells.

Since Montagnier’s new virus came from an AIDS patient with lymphadenopathy, he dubbed it “lymphadenopathy-associated virus” or LAV. This particular isolate of LAV was named “Bru.” Interestingly, Montagnier later obtained a biopsy from another AIDS patient who was infected with HTLV, as well as with the virus that he called LAV. If this had been the first patient sample, results might have been very confusing indeed.

Returning now to Gallo, concurrently and independently of Montagnier, he too was attempting to isolate a retrovirus from biopsies of AIDS patients. The sequence of events which then transpired was truly bizarre, beginning with the fact that while Gallo was seeking to isolate an AIDS retrovirus, he received a sample of Bru from Montagnier. Shortly afterwards, Gallo announced that he had isolated a retrovirus from an AIDS patient pool in his laboratory. 5 Moreover, Gallo’s isolate had somewhat different properties from those earlier ascribed to Bru. For example, unlike Bru, which grew only in fresh T cell cultures, Gallo’s isolate also grew in permanent T-cell lines. Bearing in mind Gallo’s premise that AIDS is caused by an HTLV variant, he reported that he had isolated a second type of AIDS retrovirus, which he named HTLV-III.

Here now is the crucial part of our story. When the nucleotide sequence of HTLV-III was determined afterwards, it turned out to be essentially identical to that of another LAV sample that had been isolated earlier in Montagnier’s laboratory. This finding was remarkable since HIV has an extraordinarily high mutation rate. And, since an untreated HIV-infected individual can produce between 108 and 1010 new virus particles each day, it would be extremely improbable to obtain virtually identical isolates from two different patient samples.

Considering the enormous importance of the discovery of the virus responsible for AIDS, and the resultant accolades that would surely go to its discoverer, the fact that Gallo’s HTLV-III was identical to a LAV isolate from Montagnier’s laboratory resulted in accusations flying back and forth between the two men. And, in part because of the sensational nature of AIDS itself, the competing claims of Gallo and Montagnier led to likewise sensational accounts of their controversy in the media of the day.

Now might be a good time to comment on the fact that Montagnier and Gallo gave different names to their AIDS isolates; LAV and HTLV-III, respectively. Importantly, the discoverer of a new virus is generally accorded the privilege of naming the virus. So bearing in mind the competing claims of Gallo and Montagnier, if the scientific community were to designate the AIDS virus as either LAV or HTLV-III, it would have been tantamount to recognizing Montagnier or Gallo, respectively, as its discoverer.

Harold Varmus, as chairman of the Retrovirus Study Group of the International Committee on Taxonomy of Viruses (ICTV), was mainly responsible for arriving at an outcome to the naming dispute that was acceptable to both protagonists, settling on “human immunodeficiency virus,” or HIV, as the AIDS virus is now universally known. [The story of how the naming issue was resolved will soon be covered in a separate posting.]

The fact that HTLV-III was identical to LAV, taken together with subsequent events, ultimately resulted in Gallo’s integrity being questioned and his reputation being compromised. We begin this part of our tale at a September 1983 Cold Spring Harbor meeting, ostensibly organized to discuss retroviruses in human leukemias. At this meeting, Montagnier reported isolating LAV from three AIDS patients; a homosexual, a hemophiliac, and a Haitian. Moreover, Montagnier also pointed up key differences between LAV and HTLV-I and -II. As for Gallo’s response to Montagnier’s presentation, some conference attendees described it as scornful and arrogant. In addition, in the introduction to the conference proceedings, which Gallo wrote, he brought up HTLV-III, although he never actually spoke about HTLV-III at the meeting. And, apropos the two meanings of “L” in the HTLV acronym noted above, it was in Gallo’s introduction to these proceedings that he subtly changed the meaning of “L” from “leukemia” to “lymphotropic.”

Next, in April 1984, Margaret Heckler, President Ronald Reagan’s Health and Human Services Secretary, hastily called a press conference to publicly announce that Gallo had discovered the AIDS virus. Heckler then introduced Gallo, who confirmed the discovery, while neglecting to mention that Montagnier had isolated the same virus. Gallo also managed to avoid questions from reporters who were primed to raise this issue. [In an interesting sidelight, Heckler confidently announced to the press that an AIDS vaccine would be available within two-years-time, leaving every scientist in the room aghast. Her rash optimism regarding an AIDS vaccine may well have been based on the earlier successes of Jonas Salk and Albert Sabin, who developed the killed and attenuated polio vaccines, respectively. (Salk and Sabin, like Gallo and Montagnier, were also bitter rivals; the topic of a future post.) Some have suggested that Heckler’s prediction of the vaccine was meant to distract attention from Reagan’s earlier silence on AIDS. The U.S. government indeed appeared to be indifferent to what was perceived by the public as a gay disease.6]

On the same day that Gallo announced his discovery of the AIDS virus at the press conference noted above, he also filed a U.S. patent application for a blood test that would detect signs of the virus in people. Gallo’s patent application became another sore point in his controversy with Montagnier, since the latter charged that Gallo’s blood test made use of a virus that was isolated at the Pasteur Institute. And, considering that the patent was estimated to be worth about $100 million per year, even the governments of the United States and France weighed in on the dispute. In fact, to end the disagreement over patent rights to the blood test, and so enable the U.S. and France to share proceeds from the patent equally, U.S. President Ronald Reagan and French Prime Minister Jacques Chirac signed a declaration that Gallo and Monatagnier were co-discoverers of the virus.

Here now is an example of politics intruding on science. As a condition of the agreement signed by Reagan and Chirac, Gallo and Montagnier had to write a history of the discovery of HIV that was in the accord with the agreement. What’s more, Gallo and Montagnier were forbidden from later publishing any statement that might undermine the agreement. Nevertheless, and irrespective of the political settlement of the patent rights to the blood test, the patent dispute also worked to undermine Gallo’s standing, not only because of persisting questions regarding the origins of the virus on which the test was based, but also because some of Gallo’s critics contend that his patent claim delayed use of the blood test for a year.

Considering that the undermining of Gallo’s standing began with the finding that his HTLV-III was virtually identical to a virus isolated in Montagnier’s laboratory, how did it happen that isolates of a highly mutable virus, from laboratories more than 3,000 miles apart, were virtually identical? Here is what many believe to have been the likely scenario. After Montagnier isolated Bru in Paris, he then isolated HIV from biopsies of several other AIDS patients. One of these isolates, called “Lai,” replicated much more rapidly than Bru, as well as other HIV isolates, in cell culture. Unbeknownst to Montagnier, Lai then contaminated and overgrew stocks of Bru in his laboratory. Then, Montagnier sent a sample of Bru to Gallo that unknowingly was contaminated with Lai. Next, Lai contaminated the culture that Gallo’s research group thought contained a virus that originated in their pool of AIDS patient biopsies. 7

Apropos the above, such mix-ups are not uncommon (a warning to beginning researchers). In fact, Montagnier also sent Lai-contaminated LAV samples to several other laboratories, and Lai likewise contaminated cell cultures in those laboratories. But, before entirely absolving Gallo of any culpability, we well might ask why he did not compare his HTLV-III to the sample that Montagnier had sent him, before announcing that he had discovered a new virus.

The virtual certainty, that a Nobel Prize would go to the scientist recognized as the discoverer of the AIDS virus, was for sure a major factor behind the bitter rivalry between Gallo and Montagnier. As it was, in 2008, 25 years after the first article describing HIV and its causal link to AIDS, 8 the Nobel Prize for Physiology or Medicine was awarded to Luc Montagnier and his co-worker, Francoise Barre-Sinoussi, for discovering the AIDS virus. Harold Zur Hausen shared in the award for his work identifying human papilloma viruses as the cause of cervical carcinoma. Gallo was not included in the award.

Was the decision of the Nobel Committee to exclude Gallo from the award correct? The Committee stated that Barre-Sinoussu and Montagnier “made the most important contributions to the discovery.” The Committee did acknowledge Gallo’s “detection of a novel…virus from a vast number of patients with AIDS or pre-AIDS in 1984…[which] showed considerable similarity with LAV-1.” Those findings of Gallo, taken alone, may not have justified a Nobel award. Importantly, however, the Nobel Committee did not acknowledge that Gallo’s group had been responsible for much of the basic research that made the discovery of HIV achievable. As noted above, Gallo’s group discovered IL-2, which made it possible to grow T cells in culture and, consequently, HIV as well. [One source I came across claimed that Gallo himself was unimpressed by Doris Morgan’s discovery of IL-2, and discouraged her from working on it, and that Gallo did not see any value in growing T cells.] Moreover, these breakthroughs enabled Gallo’s group to also isolate HTLV-1 and HTLV-II, thereby demonstrating the existence of human retroviruses and, what’s more, the feasibility of isolating them. And it was Gallo who first suggested that AIDS might be caused by a retrovirus. Furthermore, Gallo’s group was also the first to grow HIV in an established T-cell line, which was crucial to the development of the blood test for HIV. Additionally, Gallo’s group provided the more definitive evidence that HIV is indeed the etiologic agent of AIDS, as based on their repeated isolation of HIV from patients with AIDS and, subsequently, by means of the blood test.  Also note that Montagnier was quick to acknowledge that Gallo deserved the award as much as he and Barre-Sinoussi.

Gallo said it was a “disappointment” not to be included in the Nobel award, but he affirmed that all three of the recipients deserved the honor. Jay Levy, at the University of California, San Francisco (UCSF), is also recognized as a co-discoverer of HIV, which he originally termed the AIDS-associated retrovirus, or ARV. Levy is not as well known as Gallo and Montagnier, in part because he was not involved in their controversy. Levy reacted to being passed over by the Nobel Committee with the gracious comment: “In the end, what they (the Nobel Committee) did was quite, quite fair…And I congratulate them (Montagnier, Barre-Sinoussi, and Zur Hausen).”

Considering the importance of Gallo’s ground-breaking work, what might really have been behind the Nobel committee’s decision to exclude him from the award? Even if the Nobel committee did not regard Gallo’s contributions as equal to those of Montagnier and Barre-Sinoussi, weren’t they still worthy of the Nobel Prize?

Questions concerning Gallo’s integrity may have worked against him in the eyes of the Nobel committee; most importantly those arising from the virtual identity of Gallo’s HTLV-III and Montagnier’s earlier LAV-1 isolate. Other researchers also had concerns regarding Gallo’s ethics. Consequently, in 1990, to get to the bottom of the origin of HTLV-III, the Office of Scientific Integrity at the National Institutes of Health authorized a group at Hoffmann-La Roche to analyze HIV samples isolated in the laboratories of Gallo and Montagnier between 1983 and 1985. The conclusion of the Roche group, published in Nature in 1993, was that Gallo’s HTLV-III indeed had originated in Montagnier’s laboratory. 9 But, the group also concluded that the initial mix-up, Lai in place of Bru, occurred in Montagnier’s laboratory. The Lai-contaminated sample that Montagnier then sent to Gallo subsequently may have contaminated the culture that Gallo was working with in his laboratory.

In the end, the Roche investigating team dropped all charges against Gallo. However, before publication of their findings, Gallo’s group was found guilty of “minor misconduct” by the Office of Scientific Integrity in 1991. Thus, while the Roche team cleared Gallo of all charges of misconduct, his reputation had already been tarnished by the accusations against him. Moreover, questions still remained, particularly those pertaining to Gallo having grown Montagnier’s LAV in his own laboratory, before he reported isolating HTLV-III. What’s more, there is evidence that a micrograph published by Gallo that is said to show HTLV-III, actually depicts Montagnier’s LAV.

A second reason suggested for the Nobel committee’s slight to Gallo concerns his ego and fiercely competitive nature. Still, while Gallo’s personality may not have endeared him to the Nobel committee, it most certainly should not have precluded his contributions from being recognized by them.

Here then is another possible take on the Nobel committee’s decision to leave Gallo out of the award, as noted at the time by Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. “The committee has a long history of awarding the prize to the person or group that makes the first seminal observation or discovery, and they did that in this case.” Hence, in the end, it may simply have come down to who the committee considered to be the actual discoverer of HIV.

So, who actually discovered the AIDS virus? The answer is that HIV was first isolated by Françoise Barré-Sinoussi in Montagnier’s laboratory at the Pasteur Institute, in collaboration with other French clinicians and researchers, including Jean-Claude Chermann, Willy Rozenbaum, David Klatzmann and, of course, Montagnier. They published their findings in Science, in May 2003; about a year before anyone else. 8 Jean Claude Chermann, the second author of the Science paper, is considered by many to be equally deserving of the Nobel Award. Chermann supervised Barre-Sinoussi in Montagnier’s laboratory, and had the idea of focusing efforts to isolate HIV on patients with lymphadenopathy.

This remarkable photograph was taken in the park of the Institut Pasteur Annex in Garches, near Paris, during a break of a "100 guards meeting" in 1987. From left to right: Jonas Salk, Jean- Claude Gluckman, Jean-Claude Chermann, Luc Montagnier, Robert Gallo, Françoise Barré-Sinoussi, Willy Rozenbaum, Charles Mérieux.
This remarkable photograph was taken in the park of the Institut Pasteur Annex in Garches, near Paris, during a break of a “100 guards meeting” in 1987. From left to right: Jonas Salk, Jean- Claude Gluckman, Jean-Claude Chermann, Luc Montagnier, Robert Gallo, Françoise Barré-Sinoussi, Willy Rozenbaum, and Charles Mérieux.

Also note that, in 1985, Montagnier’s research group, in collaboration with physicians in Lisbon and virologists from Hopital Claude Bernard in Paris, also discovered HIV-2 (which they initially dubbed LAV-II) in West African patients with AIDS. Concurrent with the above efforts, Jay Levy and colleagues at UCSF demonstrated that HIV is present in AIDS patients and in healthy carriers as well.

Still, consider the following. First, the issue of which research group was the first to isolate HIV was resolved by the early 1990s. Second, Howard Temin and David Baltimore had to wait a mere five years after announcing their discovery of reverse transcriptase before receiving their Nobel Prizes. 2 So, bearing in mind the enormous significance of the discovery of HIV, why did 25 years elapse before the Nobel committee rewarded that discovery? Can it be that it was concerned with, and needed to resolve some of the ethical issues noted above? Or, was it simply that the Nobel committee tends to steer clear of controversies? Since the Nobel committee’s deliberations are shrouded in secrecy, we can only speculate on the reason for the 25-year hiatus, and why Gallo was excluded from the prize.

Next, bearing in mind Gallo’s extensive experience as a retrovirologist and that only his group had ever isolated a human retrovirus, as well as all of the resources available to him at the NIH, why didn’t he succeed in isolating the AIDS virus ahead of Montagnier?  Was it because he was fixed on the notion that AIDS is caused by a virus closely related to HTLV-I and –II? Indeed, until May 1983, Gallo was looking only for, and reporting only isolates that were like the HTLVs. So, perhaps there is the irony that if Gallo’s group had not discovered HTLV-I and -II, it might well have been the first to discover HIV.

The controversy between Gallo and Montagnier has long since subsided (although some sources state that the animosity between them remains), and they appear to be in agreement on all major issues. For his part, Gallo has stated that he never claimed to have discovered HIV, but rather claims credit for demonstrating that it is the cause of AIDS. Montagnier concedes that Gallo’s evidence in that regard was more convincing than his own. Regardless, efforts of these two individuals resulted in the identification of a new retrovirus as the cause of AIDS, and made it possible to grow large enough amounts of the virus to enable further studies. Moreover, their discovery quickly resulted in a blood test for HIV, and opened up the development of anti-retroviral drug therapies for HIV-positive individuals.

One fundamental lesson learned from these experiences was well stated in a report jointly written by Gallo and Montagnier: “Our experience with AIDS underscores the importance of basic research, which gave us the technical and conceptual tools to find the cause less than three years after the disease was first described.” 3

1 Doris Morgan, working in Gallo’s laboratory, discovered a T-cell growth factor that enabled her to grow T lymphocytes in culture for extended periods. Kendall Smith, at Dartmouth, followed up Morgan’s observations, isolating interleukin-2 (IL-2) as the T-cell growth factor that Morgan detected.

2 Howard Temin: In from the Cold (on the blog)

3 Gallo, R C., and L. Montagnier, (2003) The Discovery of HIV as the Cause of AIDS, N. Engl. J. Med. 349:2283-2285.

 4 Luc Montagnier-Biographical, at, The official web site of the Nobel Prize.

5 Mikulas Popovic, in Gallo’s laboratory, proposed isolating the virus from a pool of 10 different AIDS patient biopsies. His reason was that the pool should yield the most viable virus, by a process akin to natural selection.

6 Even the media shied away from covering the AIDS epidemic during its early years. When news stories about AIDS did appear in newspapers, they tended to be buried in the back pages, and AIDS stories were seldom reported on television. This was largely because it was difficult for the media of the day to talk openly and honestly about sex; particularly gay sex. The watershed event that changed this state of affairs was actually the July 1985 disclosure by movie star Rock Hudson that he was suffering from AIDS. Hudson was the first major public figure to reveal that he had AIDS, and his celebrity status put AIDS on the front page. The press now covered AIDS with gusto, and they had photos of Hudson to add pizzazz to their stories.

Younger readers may get an accurate glimpse of the homophobia and public attitudes towards AIDS during the early years of the AIDS epidemic from the 1993 movie Philadelphia, which often appears on TV. The main character, played by Tom Hanks, is a brilliant lawyer who is set up to be fired from his prestigious Philadelphia law firm when it discovers that he has AIDS. He then sues the firm, basing his case on the Americans with Disabilities Act of 1990, which prohibits discrimination against any individual with a disability, including those living with HIV/AIDS.

7 Slow-growing HIV isolates like Bru tend to be present at early stages of HIV infection, whereas rapidly growing viruses like Lai are seen in late stage infection. Also, the slow-growing isolates like Bru are not readily transmissible to permanent T cell lines, whereas fast-growing isolates like Lai are. This was important in the current context, since only some viral isolates from patients with fully developed AIDS could be grown in permanent T cell lines, as soon would be learned. The fast-growing strains also induce the formation of large syncytia. For details on the relevance of these points to infection in vivo, see Virology: Molecular Biology and Pathogenesis.

8 Barré-Sinoussi, F., J.C. Chermann, F. Rey, M.T., Nugeyre, S., Chamaret, J., Gruest, C Dauguet, C. Axler-Blin, F. Vézinet-Brun, C. Rouzioux, W. Rozenbaum, and L. Montagnier, (1983) Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS), Science 220: 868-871.

9 Chang, S-Y. P., B. H. Bowman, J. B. Weiss, R. E. Garcia, andT. J. White, (1993) The origin of HIV-1 isolate HTLV-IIIB, Nature 363: 466–469.

Sidney Brenner: “Only Joking”

In earlier postings 1, 2, we separately encountered Sidney Brenner and Max Delbruck, each of whom possessed a singularly strong personality.  Now, we encounter them together in a short anecdote, in which Brenner defines the “perfect practical joke” and proffers an example. The victim is Max Delbruck.

We glimpsed Sidney Brenner’s mischievous sense of humor in The Phage in the Letter. The current tale begins now with his comment: “I have always wanted to invent the perfect practical joke.” Acknowledging that practical jokes can often be cruel, Brenner tells us that his criteria for the perfect practical joke are that it “should have an economy and convey enough of the conjurer’s art so that nobody is totally dismayed.” 3

Perhaps to ease any guilt he might have felt over the episode recounted here, Brenner hastens to tell us that Max Delbruck, the victim, was himself a great player of practical jokes. And, apropos this particular tale, he also tells us that Delbruck liked to arrange for people to attend lectures for the purpose of embarrassing them there.

Brenner saw the opportunity to turn the tables on Delbruck when he (Brenner) was invited to give a talk at Caltech. Upon accepting, Brenner informed friends at Caltech that he preferred speaking to a small group. However, Brenner deliberately kept this slight detail from Delbruck. As the story then unfolds, when Brenner arrived to give his talk, he was escorted to Delbruck’s office, where a small group of his friends were waiting. They next proceeded to a small seminar room, presumably because his friends had adhered to his request. A few other colleagues were waiting there and, without further ado, Brenner launched into his talk.

Sydney Brenner in 1962
Sydney Brenner in 1962

Bearing in mind Brenner’s stature and, consequently, the large turnout expected for his lecture, Delbruck was understandably confused by what was transpiring. So, he got up and left the room to check the notice board to see what room had been reserved for Brenner’s talk. Through a crack in the door, Brenner could witness Delbruck’s bewilderment. A large lecture hall indeed had been reserved for Brenner’s lecture, and some 300 listeners were already seated there waiting to hear it.

Brenner describes what then transpired in the small room, as follows: “Seizing the opportunity, I immediately increased speed, took off my jacket and began to settle in for a full hour. Max returned, puzzled by what he should do next; the looks of dismay had turned to panic and people had started to signal to each other.” Well, Brenner was eventually stopped and the small group proceeded to the large lecture room, where “Max merely signaled me to talk with a limp wave and no introduction….This was perfection, as some people knew that I knew, but Max did not.”

1. The Phage in the Letter

2. Max Delbruck, Lise Meitner, Niels Bohr, and the Nazis

3. Brenner, S., Only Joking, Current Biology 8: R825, 1998.