This story began with the clash between Luc Montagnier and Robert Gallo over priority of discovery and, with it, the right to name the virus. In the midst of this controversy, Harold Varmus seized the initiative to find a universally accepted name for the virus that causes AIDS.
Our previous posting (Who Discovered HIV?) told how Robert Gallo, at the U.S. National Institutes of Health (NIH), and Luc Montagnier, at the Pasteur Institute in Paris, vied to be recognized as the sole discoverer of the AIDS virus. Montagnier named his isolate of the virus “lymphadenopathy associated virus” or LAV, because it came from a patient presenting with lymphadenopthy. 1 Gallo, in contrast, named the virus “human T-cell lymphotropic virus III” or HTLV-III, based on his belief that it was a variant of the human T-cell leukemia viruses-I and –II, which were isolated earlier in his laboratory.
It soon became clear that LAV was quite distinct from HTLV-I and –II. 2 Moreover, and improbably, HTLV-III was found to be identical to another LAV isolated in Montagnier’s laboratory. What’s more, Montagnier had sent a sample of his virus to Gallo before Gallo reported isolating HTLV-III. These events led to recriminations flying back and forth between Montagnier and Gallo, and, not surprisingly, to a bitter rivalry between them, as each held fast to his claim for priority of the discovery.
For the sake of completeness, Jay Levy, at the University of California, San Francisco (UCSF), was also among the first to isolate the AIDS virus, which he named the “AIDS-associated retrovirus” or ARV. Levy did not take part in the dispute between Gallo and Montagnier and, consequently, did not receive the publicity that they did. And, while Levy did not contend for recognition with the fervor of Gallo and Montagnier, his designation for the AIDS virus, and other proposals as well, also had to be considered in the deliberations described below.
The discoverer of a new virus is generally accorded the privilege of naming it. Consequently, the name that the scientific community might ultimately adopt for the AIDS virus could have implications beyond merely providing an appropriate designation for it. Specifically, if the scientific community were to acknowledge LAV or HTLV-III as the name for the virus, it would have been tantamount to recognizing Montagnier or Gallo, respectively, as its discoverer. Thus, any individuals entrusted with resolving the naming issue had to be wary of inadvertently advancing the claims of one, or the other, of the two main protagonists. There was even more at stake for Gallo, since his integrity was being called into question and, consequently, his reputation as well. Moreover, the national pride of both the United States and France were also at issue, as well patent rights to the blood test for the virus.
Although it was clear to all that HTLV-III (or LAV) is distinct from HTLV-I and –II, and that HTLV-III and LAV are one and the same virus, Gallo still went all-out to preserve HTLV-III as the designation for the virus. So, for a time, the awkward solution of the scientific community was to call the virus LAV/HTLV-III, as was recommended by the World Health Organization, or HTLV-III/LAV, as preferred by the U.S. government.
Harold Varmus now steps up to become the key player in the resolution of the naming dispute. But first, here is his bio in brief. Varmus, born in 1939, shared a 1989 Nobel Prize with Michael Bishop for demonstrating that retroviral oncogenes (e.g., v-src) have their counterparts (proto-oncogenes; e.g., c-src) in normal cells. 3 In turn, this led to the realization that mutations in particular host genes, or the inappropriate expression of those genes, might be the underlying basis for human cancers.
Harold Varmus (1981)
To appreciate the huge significance of Varmus’ and Bishop’s 1976 findings, bear in mind that most of the scientific community of the day were skeptical of the notion that cancer had a genetic basis, until Varmus and Bishop provided direct evidence in its support. Moreover, as Varmus later stated: “In recent years, after our prize was awarded, mutant proto-oncogenes and the proteins they encode have become critical tools for the classification of cancers and promising targets for drugs and antibodies-treatments that have, in some cases, proven to be effective for a significant and growing number of cancers, including leukemias and lymphomas, lung, gastrointestinal, and kidney cancers: and cancers of the breast.” 4
Varmus was a professor at UCSF during the happenings recounted here. Later, between 1993 through 1999, he served as Director of the U.S. National Institutes of Health, and from 2000 through 2010, as President of the Memorial Sloan Kettering Cancer Center. He is currently Director of the National Cancer Institute. On a personal note; I got the idea for this posting from Varmus’ brief account in his book, The Art and Politics of Science (2009). This is a marvelous book that I strongly recommend to all readers of this blog.
At the time of our story, Varmus also was serving as chairman of the Retrovirus Study Group of the International Committee on Taxonomy of Viruses (ICTV). [The ICTV, through its various study groups, has the task of developing and maintaining the commonly accepted virus taxonomy.] As chairman of his study group, Varmus assumed responsibility for resolving the AIDS virus naming dispute. To advise him in that effort, he created an international panel of eminent retrovirologists, which included Howard Temin, 5 Peter Vogt, Myron Essex, Ashley Haase, Steven Oroszlan, Natalie Teich, Kumao Toyoshima, Robin Weiss, John Coffin, and Jay Levy, as well as Gallo and Montagnier. Moreover, Varmus solicited written opinions from more than fifty additional prominent scientists and clinicians, not on his panel.
The panel was soon considering more than a dozen names. Some of these were suggested within the panel, while others were suggested by Varmus’ outside correspondents.
After the panel invested more than a year deliberating these proposed names, which included the two that Montagnier and Gallo originally adopted, it finally settled on “human immunodeficiency virus,” or HIV, as the AIDS virus is now universally known. In reaching its conclusion, the panel considered many issues, including the controversy over priority of discovery, the phylogentic relationship between the AIDS virus and HTLV-I and -II, 2 the immunosuppressive properties of the virus, and the desirability of including the term “AIDS” in its designation. Finally, the panel considered how its preferences squared with established naming conventions and precedent. Varmus, of course, mediated all discussions within his panel.
Notwithstanding all the arguments and compromises that the panel considered, Gallo was not satisfied when all was said and done, nor did the outcome end his dispute with Montagnier. 6 Although the panel’s end result essentially nullified the right of Montagnier and his group to name the virus which they believed they had discovered, Montagnier was already prepared to accept an alternative name, although not HTLV-III. In contrast, since the panel rejected Gallo’s claim that the virus was a variant of HTLV, he, unlike Montagnier, would not sign-off on the May 1986 letter the panel sent to Nature, which proposed that the AIDS virus be called human immunodeficiency virus, or HIV. [The panel also recommended subcategories of HIV. HIV-1 designates the more common type of HIV, which Gallo and Montagnier each claimed to have discovered. HIV-2 designates the less common variety seen in West Africa, which Montagnier is acknowledged to have discovered. 6]
As Varmus later related, “However difficult this process was-with leaks to the press by Montagnier, belligerent letters to me from Gallo that were copied to most of our nation’s leaders, surly and aggressive behavior by the two rivals, and refusals to sign the final statement by Gallo and his close colleague Max Essex, a virologist at Harvard’s School of Public Health-it was interesting intellectually and socially.” 4 [It’s been said that the diplomatic skills, which Varmus acquired while leading the effort to solve the AIDS virus naming dispute, served him well later in his role as Director of the NIH. For much more on Varmus in that later role see: Varmus, H. 2009. The Art and Politics of Science. Norton Books, New York, NY.]
Some of the thorny issues that Varmus’ panel had to come to grips with with were enumerated above. Those issues and additional others, were also discussed in Varmus’s written correspondences with members of his panel, as well as with the outside experts whom he consulted. 7 We now draw on those communications to glimpse the multiple points of view that Varmus and his panel had to wrestle with.
We begin by considering why the term “AIDS” was not included in the panel’s designation for the virus. This is particularly interesting, especially in view of the naming precedent for viruses such as poliovirus, hepatitis A virus, hepatitis B virus, and the influenza viruses; all cases where the virus is designated by the clinical syndrome that it is associated with. Moreover, that naming convention is generally accepted, despite the fact that in these and other such instances, only a small minority of infected individuals ever manifest the disease. What is more, taking the cases of Hepatitis A and B viruses as an example; these are two phylogenetically unrelated viruses that have nothing whatsoever in common, other than that each causes liver disease. And, as Varmus, himself, noted: “Traditional retroviral nomenclature has worked well in this regard. The convention has been to name viruses according to the host species and the prominent pathology associated with the prototypic isolate of a single type; two examples of such names are ‘feline leukemia virus’ and ‘mouse mammary tumor virus.’” 8 And, even more to the point, there are the examples of the human T-cell leukemia viruses, which have already featured prominently in this tale, and in our previous one (Who Discovered HIV?). So, why then did the panel not choose to simply call the etiologic agent of AIDS “the AIDS virus”?
Michael Gottlieb was one of Varmus’ correspondents who spoke out strongly on this issue. He, and his colleagues at UCLA, command our attention, since, in 1981, they were the first to realize that individuals suffering from persistent infections with the protozoan Pneumocystis carinini, and those with the rare cancer, Kaposi’s sarcoma, were all afflicted with the same underlying disease that specifically targeted their CD4 T cells for destruction. That is, they were the first to recognize and report the existence of the disease that subsequently was named AIDS. Here, then, is an excerpt from Gottlieb’s April 25, 1985 letter to Varmus.
“I am writing to convey my concerns as a clinician about sentiment for nomenclature which would identify the agent as the ‘AIDS virus.’ I believe that this nomenclature would be unfortunate. It is estimated that over one million persons in the U.S. alone have serum antibodies. The fully expressed AIDS syndrome is well publicized to be a lethal intractable illness associated with considerable suffering. In my view the term ‘AIDS virus’ would create considerable distress among all individuals found to have previous exposure…I am hopeful that your Study Group will also wish to avoid creating widespread social distress…” [My note: Gottlieb’s comments, as well as others quoted below, reflect that it was not yet appreciated that virtually all HIV-infected individuals would eventually succumb to AIDS. That disheartening state of affairs would begin to change dramatically with the development of antiretroviral therapy. 6]
Mark Kaplan (North Shore University Hospital), Jerome Groopman (New England Deaconess Hospital), and several other clinicians spoke on the same issue in their April 29, 1985 letter to Varmus:
“The last major aspect to consider in determining the nomenclature of this virus must be the emotions of the patient who is infected with this agent. Patients told that they have infection with the AIDS virus develop devastating psychological symptoms that have been witnessed by all clinicians dealing with these patients and their families. It is a cruel name for the virus for it leaves no hope for the patient, implying that the patient will inevitably develop and die from AIDS. If we were to have called the EB virus by the disease it was first felt to produce, it would have been called the Burkitts Lymphoma virus. By analogy, one can imagine the distress caused to a patient with EBV if told that he had the Burkitts lymphoma virus…” [My note: EBV, for the Epstein-Barr virus, is a ubiquitous herpesvirus that occasionally causes the non-fatal illness, infectious mononucleosis. It also is associated with Burkitt’s lymphoma, a malignant B-cell lymphoma seen in children living in equatorial Africa and New Guinea.]
Addressing the same issue in her April 22, 1985 letter to Varmus, panel member Natalie Teich, at the Imperial Cancer Research Fund Laboratories, wrote the following :
“Poliovirus was acceptable even though the vast majority of infected persons remained asymptomatic. However, with AIDS, the social and economic implications and stigma may be too overriding.”
Yet in the case of this issue, and others as well, there was no immediate consensus among those contributing to the discussion. Here is what Jay Levy, also a panel member, wrote in his May 10, 1985 letter to Varmus:
“The concern about frightening individuals with the term ‘AIDS’ virus should not be a consideration…no matter what term is given to the AIDS retrovirus, individuals will easily recognize its connotation.”
Levy adds the following: “I favor classifying the AIDS virus in a category by itself. It is most likely the prototype of a human lentivirus and should not be confused with other human retroviruses. My group prefers to maintain our initial nomenclature, that of AIDS-associated retrovirus (ARV) as it best defines the agent linked to this distinct clinical disease.”
Irrespective of whatever scientific merits Levy’s proposal may have brought to the table, it was not seriously considered by the discussants. For example, Natalie Teich dismissed it as follows: “With due regard for Jay, this was clearly a ‘johnny-come-lately’ claim.”
And, William Haseltine, at the Dana-Farber Cancer Institute, wrote the following in his August 7, 1985 letter to Varmus. “…Dr. Jay Levy’s proposed name has no merit as his report merely repeated the original isolations using previously published methods.”
Notice that both Teich and Haseltine rebuff Levy’s preference solely on the basis of right-of-discovery. With that in mind, here is Haseltine’s take on the appropriateness of calling the virus HTLV-III:
“I strongly favor the name HTLV-III for the virus. I would not oppose the name HTLV-III/LAV or LAV/HTLV-III. My reasons are as follows:…Unless there is good reason to the contrary, the original discoverers of the virus should have the right to call the virus the name they chose. Both the laboratories of Drs. Gallo and Montagnier have valid claims to be original discoverers of the virus. Although the Paris laboratory published first, I am convinced that Gallo had, in fact, isolated the virus at or before late 1982 to very early 1983 as did the Paris Laboratory…Given what must be considered to be a lack of consensus of the committee on the appropriate nomenclature, there is no compelling reason not to abide by the choice of the discoverers themselves…HTLV-III is a far better name than LAV. LAV refers to a specific disease state. HTLV-III does not.” [My note: This passage underscores that the controversy between Montagnier and Gallo, over priority of discovery, was still very much alive at this time.]
Anthony Fauci, as Director of the National Institute of Allergy and Infectious Diseases, also commanded attention. In his May 3, 1985 letter to Varmus, Fauci noted that he typically refers to the virus as the “AIDS retrovirus.” However, he argues against adopting that name, not quite for the reasons expressed above, but seemingly because of the mistaken belief at the time that many infected individuals will not develop AIDS. Nevertheless, even if that belief were correct, the very vast majority of individuals infected with poliovirus, and the hepatitis A and B viruses, and other viruses likewise named for the pathology with which they are associated, do not develop those diseases, as was noted above.
Fauci’s most interesting comments may be those concerned with naming the virus either “LAV” or “HTLV-III.” Regarding “LAV,” he says: “…I do believe it would be inappropriate to call this the lymphadenopathy-associated virus (LAV). The reasons for this should be obvious. First, the virus causes more than lymphadenopathy…”
Regarding “HTLV-III,” he says: “Although there are accumulating data, of which you are aware or more aware than I am, that there are significant dissimilarities between this virus and HTLV-I and –II, I still believe that there is enough reason to maintain this virus within the HTLV nomenclature that this should be continued. The reasons for this are that it surely is a human virus (H), it is a T-lymphotropic virus (TL), and it is a virus (V). Therefore, I would think that HTLV itself is a reasonable abbreviation for the virus. For that reason I would suggest naming it either HTLV-III alone or HTLV-III/LAV. However, for reasons given above concerning the disadvantage of using the terminology LAV, I would elect to call it HTLV-III.”
Fauci does not neglect to point out: “I am well aware of all the difficulties and the emotional issues that are interjected into this vis-à-vis who will get more credit related to the name that is chosen. I will try to disassociate myself from any of that and give you as objective a viewpoint as I possibly can concerning the nomenclature….”
The above comments are from but a small subset of Varmus’ correspondences. And, the comments cited above are merely a subset of the positions and arguments stated in them. Yet they enable us to better appreciate Varmus’ accomplishment in arriving at an acceptable and appropriate name for the AIDS virus, and one which did not stir up further discord. As he succinctly stated in his January 17, 1986 memorandum to his panel: “I and several committee members have come to favor HIV: it is simple; it is novel (and hence does not inflame controversies); and it is based upon the name of the disease with which the virus is readily identified, without including the term AIDS.”
I end this posting with the text of a December 19, 1984 letter from Varmus to David Kingsbury at Oxford, in which Varmus informs Kingsbury of the progress of his ICTV Retrovirus Study Group towards revising the retrovirus phylogeny. Varmus’ letter is followed by a portion of Kingsbury’s January 4, 1985 response. [Kingsbury is best known for his research on influenza viruses. I presume that Varmus was corresponding with Kingsbury here, in part because of the latter’s stature within the ICTV, which put Kingsbury in a position to help Varmus gain approval from the ICTV’s higher leadership for his study group’s recommendations.]
Thanks for your newsletter. As you probably know, we have updated the summary of Retroviridae for Intervirology (a minor task), and we are anticipating some difficulty with finding a suitable name for the AIDS virus. I am waiting for the dust to settle from the nucleotide sequencing (done or almost done in four labs at least) before convening a subcommittee. But it is clear that the AIDS virus is no more related to HTLV-I than to any other retrovirus on the basis of sequence comparison. Would you like to tell Bob Gallo it shouldn’t be called HTLV-III?
Harold E. Varmus, M.D.”
And Kingsbury’s reply:
….The news about the AIDS virus is startling! Another family of human retroviruses? When you have adequate data to take a firm position on this I will be happy to tell Bob Gallo the facts. I have no vested interest in the matter.
With best wishes,
1. As noted in Who Discovered HIV?, 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.The 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.
2. The following statement appears in Harold Varmus’ draft report (Naming the AIDS Virus), which reviews the deliberations of his panel to find a suitable name for the retrovirus that causes AIDS.
“If an evolutionary tree is established for retroviruses by comparing the order of amino acids in the protein most characteristic of retroviruses, the enzyme that converts RNA to DNA, it is apparent that the AIDS virus is most closely related to the sheep lentivirus, called visna, whereas the human T cell leukemia viruses are in another limb of the tree, more closely related to other oncogenic viruses, leukemia and sarcoma viruses of various animals, particularly the bovine leukemia virus.”
3. Stehelin, D., H.E. Varmus, M. Bishop, and P.K. Vogt. 1976. DNA related to transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170-173.
4. Varmus, H. 2009. The Art and Politics of Science. Norton Books, New York, NY.
5. For more on Temin, see: Howard Temin: In From the Cold, on the blog.
6. Who Discovered HIV? On the blog.
7. The Harold Varmus Papers, AIDS and HIV: Science, Politics, and Controversy, 1981-1993: Documents
8. Harold Varmus’ April 10,1986 draft of his report, Naming the AIDS Virus, which reviews the deliberations of his panel to find a suitable name for the retrovirus that causes AIDS.