HIV/AIDS Research: Its History & Future Meeting
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Max Essex: Okay. Thank you. I'm going to talk about a little bit more than [just] feline retroviruses, but I will talk about them. Okay. I think Robin [Weiss] mentioned that the first evidence of feline leukemia virus was by Bill Jarrett (1928–2011, veterinary pathologist) published in 1964, which was absolutely true. (1) What he did was ground up tumor masses, lymphoid tumors, [00:00:30] inject them into young cats or kittens or almost-newborn kittens, and see both what we now call retrovirus particles, virus-like particles, he called then.

The one limitation perhaps was that the preparations weren't entirely cell-free, so some wondered if there might be a cellular transmission. [00:01:00] Then, about three years later, Tom Kawakami published this paper (2) which was really on cell-free and extended the discovery of Bill Jarrett. Kawakami, who happened to be my PhD professor, was trained as a biophysicist and had a background in purifying viruses and gradients by sedimentation, coefficient, and buoyant density, and [00:01:30] everything else.

He used those tools and in essence, confirmed what Jarrett had done. Then, I sort of had the good fortune to enter this lab about a year later. A lot of work was going on in that lab at the time. I had nothing to do…with either of those, but I had a lot of opportunities to study C-type viruses and [00:02:00] feline leukemia virus (FeLV) entering the lab later.

This also happened, I think somebody—maybe John Coffin—mentioned that there was a massive expansion in the Virus Cancer Program, [the] Special Virus Cancer Program (SVCP) [era], here it was called. I just guessed these dates. (Note: dates for the three virus cancer programs is 1964–1978.) It might have been longer or started earlier. I'm not sure. That created a major expansion in funding and research [00:02:30] with the drive to identify new C-type viruses, or oncornaviruses, or retroviruses or whatever they were called then, in animal and human leukemias and lymphomas. (3)  A lot of it was by electron microscopy, by tools like massive continuous flow ultra-centrifugation to funnel through huge amounts of cow plasma, for example.

Yet, [00:03:00] it resulted in the discovery of quite a few viruses in the laboratory I was in at that time. None by me, I should point that out. But there were at least three viruses discovered in a period of a year or two. The first was the Snyder-Theilen feline sarcoma virus, which yielded the FeSV gene that Harold [Varmus] referred to in one of his slides. That was discovered by a graduate student named Stanley Snyder. (4)

Myron Elmer "Max" Essex, b. 1939, virologist and veterinarian, Chair of the Harvard T.H. Chan School of Public Health AIDS Initiative (HAI) in the Department of Immunology and Infectious Diseases. One of the first to suspect that AIDS was caused by a retrovirus, and discovered the gp120 protein of HIV in 1984 (see minute 12:00).

This talk covers the 1960s to today, and focuses on the history of veterinary virology, its relationship to oncovirus research during the War on Cancer, and the work to eliminate the HIV/AIDS outbreak in Botswana.

 

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The second was the [00:03:30] Simian sarcoma virus (SSV), which yielded another oncogene maybe you spoke about, discovered by another graduate student named Dan Gould. (5) The third was the Gibbon-ape leukemia virus. In retrospect, it seemed to me remarkable that those discoveries—nothing I did at the lab at the time—those discoveries, which were all published in Nature or Science or something, received little to no attention in the community. People largely forgot about them. [00:04:00] Here, we had served up a couple of primate retroviruses and feline sarcoma virus in an outbred cat and there was very little attention paid to it.

I think that was partly because so much of the emphasis or the leadership in this Special Virus Cancer Program by people like George Todaro (b.1937)  and [Robert] Huebner (1914–1998, one of the early leading theorists of viral carcinogenesis) were focused almost completely [00:04:30] in their leadership on viruses of inbred mice where they—there's a series of papers of which I've only cited two (see cit. 3)—where they spoke about how retroviruses causing leukemia were genetically inherited as virogenes and oncogenes, but not just as oncogenes, rather than transmitted as infectious agents [i.e. oncoviruses]. (Editor's note: Essex may be trying to say, "as virogenes and oncogenes, but not just as oncogenes, rather than as infectious agents like oncoviruses.")

So, it surprised a lot of people, [00:05:00] I think you could say when we—and by we, I mean, three separate laboratories, were all collaborating together, 1) the laboratory Bill Jarrett, 2) the laboratory of Bill Hardy at Memorial Sloan Kettering in New York and 3) our own, all published at about the same time, in fact, we were all collaborating and all co-authors on each other's papers—that the cat leukemia viruses were clearly infectiously transmitted [00:05:30] as contagious viruses. I don't think after that, there was any question about that. (6) That, too, though, didn't generate as much attention as we thought it deserved by most investigators, but one who I have to say paid a lot of attention to it rapidly was Bob Gallo.

#scientific competition and collaboration

Then, soon after that, within a couple of years or so, we published a bunch of papers. Again, all three laboratories, all doing similar [00:06:00] stuff showing that these feline leukemia viruses caused immune suppression. (7) Indeed, they killed more cats through opportunistic infections that looked remarkably similar to some of the human diseases like pneumonia, candida oral, stomatitis infections, things of this sort. It would only be much later as somebody else mentioned, in 1987 that Niels Pedersen [00:06:30] identified a FIV lentivirus, and that ironically didn't seem to cause as much disease or be as transmissible as did the feline leukemia virus. (8)

Now, if we then move onto the period of human retroviruses. I was one of the people who learned about this first perhaps outside of Bob [Gallo]'s lab, because I was [00:07:00] on a committee to review his lab. After publication or recognition of HTLV-I (9) he rapidly sent us cultures to use in our own studies, because one of the first things we were asking was: In this disease in South-Western Japan, was the HTLV also causing immune suppression? not AIDS, just immune suppression in its own right, [00:07:30] in the same sense that cat leukemia virus caused immune suppression in cats that were at risk.

We found indeed that it did, which we published a couple of years later with Nobuyoshi Tachibana who was on sabbatical from Kyushu, Japan, in our lab. (10) Then, of course, rapidly after that, came the first clinical descriptions AIDS. (11) and I think they all go into [00:08:00] more detail on that—I think Mike Gottlieb is here and we'll hear a lot more about that from Jim Curran or Paul Volberding or somebody.

Then, in 1982, I first got involved in the so-called AIDS research, and it happened because I was invited to a number of these workshops at NIH and maybe CDC where there were all kinds of [00:08:30] hypotheses proposed for the etiology of AIDS. There were hypotheses about amyl nitrate and butyl nitrate “poppers” causing the disease, about autoimmunity from repeated exposure to sperm. And these actually received a lot of attention, they didn't seem out of line at the time. Of course, an infectious etiology where a whole range of agents were considered, but a lymphotropic virus that might be related to [00:09:00] HTLV-I was one that was proposed by certainly Bob Gallo and I. Then, in about the same time 1982, 1983, there was recognition of AIDS in a whole bunch of other groups like injection drug users, hemophiliacs, transfusion recipients, et cetera, and I think Jim Curran will be going over that.

 

Now, there's the Science of May 20, 1983 [00:09:30] that had the first papers on any of this. (12) They talked about identifying a virus in association with HIV/AIDS, we then called GRID, or something else. The first paper, interestingly enough, had nothing to do with human AIDS. That was another paper on the cat system from our laboratory on some of the details on how the antibody response could be suppressed by the feline leukemia virus. [00:10:00] The last paper, which I'm sure you'll hear more about, it was from Françoise Barré-Sinoussi and Luc Montagnier (b. 1932), and I think she's going to talk about that. And then were two papers by Bob Gallo and there was this paper by us.

And the paper by us used proteins in cells from HTLV-I affected cells, and sera from AIDS patients and controls sent to us by CDC on the code. What we found was that about a quarter [00:10:30] of the AIDS patients clearly had antibodies that precipitated proteins and amino acid precipitation of HTLV, and about 75% didn't, but the controls didn’t. And it was sent on the code and we couldn't quite figure out what that meant. Jean Marx wrote a Science research news article at the time and gave me this quote—which I must [00:11:00] admit, I just found it when I looked back earlier this week at these papers. What it said is, "I definitely do not want anyone to get the impression that we have proof of cause. What we do have is a good lead." (13)

#early names for AIDS — gay cancer, gay pneumonia, GRID, 4H, KSOI, slim disease, etc.

#models (model systems, model organisms, modeling)

 

#antibody test, antigen test, serological test, serology

Then, of course, about a year later, came these series of papers from Gallo, which I think, by any criteria, had to be considered as the proof of etiology. (14)  But another [00:11:30] shocking thing about working in this area, for me at least, was how long it took for so many in the scientific community to accept that, because the evidence, by any criteria, for those of you who are familiar with epidemiology at least, it was absolutely overwhelming. Yet, across, there are some that may still not accept it today, but not very many [00:12:00].

Okay. Now [1984–1985] there were a lot of things going on and it was a mad flurry of work in all of our laboratories at that time. Some of the things we were involved in was actually published later in 1984 based on the cell lines and the proteins we identified in those cell lines. The then-HTLV-III or [00:12:30] HIV-infected cells that Bob Gallo gave us, identifying that gp120 is a key antigen he used for blood screening. (15) We used the technique for that, that seemed remarkably creative at the time—we certainly didn't invent it—It was radiolabeled amino acid sequencing, which simply allowed you to add on radioactive cysteine and methionine to this cell culture system and then [00:13:00] match the sequence of the amino acids read out from the amino terminus end to the sequence for the virus, which by that time, was being generated by Flossie Wong-Staal and Bill Haseltine (b. 1944), et cetera. Using that, we could verify fairly rapidly that gp120 really was the envelope protein of the virus. That was not expected by almost anybody because all of the other glycoproteins [00:13:30] and viruses of retroviruses were much smaller than that.

Then, at some point, at the same time that was going on, we had a call from Ron Hunt, who was the director of the New England Regional Primate Center. He asked us if we would collaborate and come out and look at this outbreak of what was ultimately called simian AIDS at the New England Regional Primate Center. We did and we collaborated with Ron Desrosiers  [00:14:00], [unintelligible 00:14:01], and others. This is Phyllis Kanki (virologist and epidemiologist) who was a doctoral student in my lab at the time. That resulted rapidly in the identification of the SIVs with these two back to back papers in Science. (16)

 

 

 

At the same time that was going on, we screened sera from wild monkeys in West Africa because of the collaboration we had set up with Souleymane M’Boup (b. 1951, Senegalese microbiologist at the University of Dakar, one of the discoverers of HIV-2) and others and found that a large fraction of monkeys [00:14:30] in West Africa had antibodies to HTLV that were cross-reactive. (17)

Then still, remarkably, within 1985 to 1986, we had the first evidence that I think Robin referred to as identification of HIV-2 in West Africans based on serologic responses. (18–19) This is [00:15:00] radio-immunoprecipitation with different serum samples from US, United States AIDS patients. This is West African AIDS patients. United States AIDS patients here, West African AIDS patients.

What you see is the West African AIDS patients reacted much better with the envelope of the monkey virus than they did with [00:15:30] HTLV-III or HIV and vice-versa. The US patients, of course, reacted much better with gp120/160, whereas the West African patients did not. That suggested quite clearly that the virus of people in Senegal in West Africa was different. We called it HTLV-IV, which obviously didn't go very far. [chuckles] [00:16:00]

Then, about that time, well, a little bit later, to be fair, in the early to mid-1990s, I was struck by what was going on with the epidemic in Southern Africa. It was well known by everyone by that time that there was a massive epidemic in sub-Saharan Africa, but what really wasn't appreciated very much was how different the epidemic was in Southern Africa as opposed to the rest of [00:16:30] sub-Saharan Africa, really, all other developing countries outside of the region in South America, Asia, whatever, where rates were really quite low.

We thought something must be different there. It was clear fairly early on that it was a different subtype of HIV, then called subtype C. As you can see here from just charts that came up somewhat later from the World Health Organization [00:17:00] talking about the prevalence in different countries, according to the UNAIDS.

What is clear is that all of them above a line of about 6% or 7% or 8% in the range of 10, or 12, or 15, or 25, are all countries in Southern Africa with HIV-1 C and all countries in Southern Africa have such a massive [00:17:30] epidemic. It struck us that something strange was going on there.

Partly because of that, I had an introduction. I forced an introduction, I guess you could say, to the then-president of Botswana, [Festus] Mogae (b. 1939, in office 1999–2008), and negotiated an arrangement with him to build a laboratory in the country to make a long-term commitment, which we have and was still there. [00:18:00]

The laboratory was built in part by the government of Botswana in exchange for our serving as a reference lab on the ground floor ,with the other floors being research floors, for tests that are done for proviral DNA in infants now, and initially antibody credibility for infection, and viral load, and all those sorts of things.

So, that's the commitment we made early on [00:18:30] in turn for their putting up some of the money for the building and a little bit each year for the program. Merck & Co., Inc. (Merck Sharp & Dohme) and Gates Foundation also contributed significant amounts into the program, of course, still goes on.

One of the first things we did with the program was concentrate on mother-to-child transmission because there was early evidence in this ACTG trial 076 (1991–1994), which we were not involved on—it was done in the US and Europe—to show that [00:19:00] AZT (azidothymidine) could reduce mother-to-child transmission, at least from in utero of birth transmissions. (20) And rates and pregnant women in Botswana were extremely high, about 50% in those who were 25 to 29, about 37% to 38% overall.

So we spent some time studying those things. This was a paper actually from a collaboration we had [00:19:30] in Thailand showing that longer uses of drugs during pregnancy or in the infant early on reduced transmission even more. (21) This was one that showed that you can breastfeed safely. (22) This is one by Roger Shapiro in our group showing that earlier trimester use of triple drugs reduced transmission tremendously, by about 99%. (23)

I was thinking about how impressive [00:20:00] those results became in Botswana, because this (23) is a series of more than 3,000 samples that Roger Shapiro and Dan Kuritzkes working with us now and examined in random births in hospitals in Botswana and of 3,000 pregnant HIV positive women, 18 of them were positive. So, with this as the national program itself is very successful [00:20:30] in reducing transmissions from positive mothers to below 1%, which I think is remarkable progress. I'm not claiming any intellectual credit for it, but I think it's remarkable progress.

 

 

 

We were also involved in the site in Botswana in the [Myron] Mike Cohen (b. 1950) [HPTN] 052 Study (2005–2015), (24) which Science billed as, "The Breakthrough of the Year," (25) and that was a study that simply showed that if you gave [00:21:00] drugs to the HIV-positive partner in a discordant couples relationship with the other partner who was uninfected, it was extremely effective in preventing transmission between those partners.

Now, finally, I just wanted to mention a very current stuff which is based on the World Health Organization goals of the 90-90-90 program to reduce transmission [00:21:30] by 90% based on a criteria where you test enough people to say that 90% of the infected people in the population know they were infected, that of those who know they're infected, 90% will be on antiretroviral therapy, and that those that are on antiretroviral therapy, 90% should be in complete viral suppression.

HPTN Study 052 (2005–2015)

We are now conducting a very large village [00:22:00] randomization trial to look at that. Based on our baseline data, Botswana is at least second, probably second in the world in reaching that goal after Sweden that's already reached it. So, as of 2015, this is a description of the study, but as of 2015 data, we were at about 70.2% with a goal of 73%. (26) [00:22:30] This is compared to the US, which is pretty bad. Although, some sites wouldn't leave us--

So, for future directions for AIDS in Africa, and I'm not going to tell you I have any answers about cure or that sort of thing, but I would say massive implementation of the WHO 90-90-90 guidelines with treatment as prevention for all seems obvious. Treat on the basis of viral load [00:23:00] when you can't treat all. Don't worry about T4 lymphocyte counts. Point-of-care viral load tests are available. PrEP (pre-exposure prophylaxis) for those who are exposed to untested populations thought to be at high prevalence. Move as many people as possible to dolutegravir because it doesn't generate drug-resistance. Botswana has already made a national commitment and is using dolutegravir as [00:23:30] first-line.

Another pet interest of ours is a better epidemiology including viral phylogenetic linkage cluster analysis to detect which foci of virus transmission in these villages in the randomized study are most involved in transmission and should be targeted for more attention for testing and treatment, et cetera. Thank you.

[applause]

Julie Overbaugh (moderator): [00:24:00] Okay. We have time for a few questions. 

Anchor
qa
qa

John Coffin: This one? Yes. You mentioned viral load testing. How widely implemented is viral load testing for ART monitoring in Africa now, not just in Botswana?

Max: It's universal in Botswana. It's not [00:24:30] as widely used in much of the rest of sub-Saharan Africa as it should be, but there's a great push by the UNAIDS Committee to make it much more available. I think with the recent progress on these point-of-care viral load tests it will be because they seem pretty good. It leads a couple of them that we've--

John Coffin: Is resistance testing making its way into Botswana? That seems to be more advanced of the African country, at least Southern African countries.

Max: Yes. [00:25:00] In fact, in this random sample, which was 20% of the households in 100,000 for those 30 randomized villages, and of those 20%, about 4,000 positive people on antiretroviral drugs, not everybody was on antiretroviral drugs, but of those who were, [00:25:30] complete viral suppression was 96.5% at the 300 or 400 level let loose, 92% of the 50 level or so. Those are distant villages in the country. It was not the big city.

Bob Gallo: Max, I just wanted to say something openly that you started as a vet and from everything I [crosstalk]

Max: So did Harry Rubin (1926–2020).

[laughter]

Bob Gallo: Well, don't say that. He denied AIDS. [00:26:00] He was one of the Nazis. Okay. Give me time to finish because I just wanted to say from everything I've heard, you've done something rather historical, like your colleague here from nearby town is doing in South Africa that you've done something really historical in Botswana.

Other people in our institute that are involved in Africa, the clinical division, all have this great off about what you've achieved. I heard it originally from Bill Haseltine, of all people, when he visited there, but I just thought everybody should know that this was a [00:26:30] kind of historical contribution what you did in Botswana.

Max: Thank you.

[applause]

[00:26:41] [END OF VIDEO]

 

 

Citations

1.  Jarrett, William F. H., William B. Martin, George. W. Crighton, R. G. Dalton, and M. F. Stewart. “Leukemia in the Cat: Transmission Experiments with Leukemia (Lymphosarcoma).” Nature 202, no. 4932 (May 9, 1964): 566–67. doi:10.1038/202566a0.

2. Kawakami, Thomas G., Gordon H. Theilen, Donald L. Dungworth, Robert J. Munn, and Sharon G. Beall. “‘C’-Type Viral Particles in Plasma of Cats with Feline Leukemia.” Science 158, no. 3804 (November 24, 1967): 1049–50. doi:10.1126/science.158.3804.1049.

3. On early cancer virus research: 

  • Huebner, Robert J., and George J. Todaro. “Oncogenes of RNA Tumor Viruses as Determinants of Cancer.” Proceedings of the National Academy of Sciences 64, no. 3 (November 1, 1969): 1087–94. doi:10.1073/pnas.64.3.1087.
  • Todaro, George J., and Robert J. Huebner. “The Viral Oncogene Hypothesis: New Evidence.” Proceedings of the National Academy of Sciences 69, no. 4 (April 1, 1972): 1009–15. doi:10.1073/pnas.69.4.1009.

4. Snyder, Stanley P., and Gordon H. Theilen. “Transmissible Feline Fibrosarcoma.” Nature 221, no. 5185 (March 15, 1969): 1074–75. doi:10.1038/2211074a0. (Note: Essex does not have this on his slide.)

5. Theilen, Gordon H., Daniel Gould, M. Fowler, and Donald L. Dungworth. “C-Type Virus in Tumor Tissue of a Woolly Monkey (Lagothrix Spp.) With Fibrosarcoma.” JNCI: Journal of the National Cancer Institute 47, no. 4 (October 1, 1971): 881–89. doi:10.1093/jnci/47.4.881. (Note: Essex does not have this on his slide.)

6. 3 papers on the infectious nature of feline leukemia virus:

  • Hardy, William D., L. J. Old, Paul W. Hess, Myron Essex, and Susan M. Cotter. “Horizontal Transmission of Feline Leukaemia Virus.” Nature 244, no. 5414 (August 3, 1973): 266–69. doi:10.1038/244266a0.
  • Jarrett, William F. H., Oswald Jarrett, Lindsay Mackey, Helen Laird, William D. Hardy, and Myron Essex. “Horizontal Transmission of Leukemia Virus and Leukemia in the Cat.” JNCI: Journal of the National Cancer Institute 51, no. 3 (September 1, 1973): 833–41. doi:10.1093/jnci/51.3.833.
  • Essex, Myron E., Susan M. Cotter, and J. L. Carpenter. “Feline Virus-Induced Tumors and the Immune Response: Recent Developments.” American Journal of Veterinary Research 34, no. 6 (1973): 809–12.

7. 4 papers on FeLV causing immune suppression:

  • Hardy, William D., L. J. Old, Paul W. Hess, Myron Essex, and Susan M. Cotter. “Horizontal Transmission of Feline Leukaemia Virus.” Nature 244, no. 5414 (August 3, 1973): 266–69. doi:10.1038/244266a0.
  • Cotter, Susan M., William D. Hardy, and Myron Essex. “Association of Feline Leukemia Virus with Lymphosarcoma and Other Disorders in the Cat.” Journal of the American Veterinary Medical Association166, no. 5 (March 1975): 449–54.
  • Essex, Myron, William D. Hardy, Susan M. Cotter, R. M. Jakowski, and A. Sliski. “Naturally Occurring Persistent Feline Oncornavirus Infections in the Absence of Disease.” Infection and Immunity 11, no. 3 (March 1975): 470–75.

8. Pedersen, Niels C., Esther W. Ho, Marlo L. Brown, and Janet K. Yamamoto. “Isolation of a T-Lymphotropic Virus from Domestic Cats with an Immunodeficiency-like Syndrome.” Science 235, no. 4790 (February 13, 1987): 790–93. doi:10.1126/science.3643650.

9. Poiesz, Bernard J., Francis W. Ruscetti, Adi F. Gazdar, Paul A. Bunn, John D. Minna, and Robert C. Gallo. “Detection and Isolation of Type C Retrovirus Particles from Fresh and Cultured Lymphocytes of a Patient with Cutaneous T-Cell Lymphoma.” Proceedings of the National Academy of Sciences 77, no. 12 (December 1980): 7415–19. doi:10.1073/pnas.77.12.7415.

10. Lee, Tun-Hou, John E. Coligan, T. Homma, Mary Frances McLane, Nobuyoshi Tachibana, and Myron Essex. “Human T-Cell Leukemia Virus-Associated Membrane Antigens: Identity of the Major Antigens Recognized after Virus Infection.” Proceedings of the National Academy of Sciences 81, no. 12 (June 1, 1984): 3856–60. doi:10.1073/pnas.81.12.3856.

11. First clinical descriptions of AIDS in 1981:

  • Gottlieb, Michael S., Robert Schroff, Howard M. Schanker, Joel D. Weisman, Peng Thim Fan, Robert A. Wolf, and Andrew Saxon. “Pneumocystis Carinii Pneumonia and Mucosal Candidiasis in Previously Healthy Homosexual Men.” New England Journal of Medicine 305, no. 24 (December 10, 1981): 1425–31. doi:10.1056/NEJM198112103052401.
  • Masur, Henry, Mary Ann Michelis, Jeffrey B. Greene, Ida Onorato, Robert A. Vande Stouwe, Robert S. Holzman, Gary Wormser, et al. “An Outbreak of Community-Acquired Pneumocystis Carinii Pneumonia.” New England Journal of Medicine 305, no. 24 (December 10, 1981): 1431–38. doi:10.1056/NEJM198112103052402.
  • Siegal, Frederick P., Carlos Lopez, Glenn S. Hammer, Arthur E. Brown, Stephen J. Kornfeld, Jonathan Gold, Joseph Hassett, et al. “Severe Acquired Immunodeficiency in Male Homosexuals, Manifested by Chronic Perianal Ulcerative Herpes Simplex Lesions.” New England Journal of Medicine 305, no. 24 (December 10, 1981): 1439–44. doi:10.1056/NEJM198112103052403.

12. 5 articles in Science, May 20, 1983 on AIDS:

  • Trainin, Ze’ev, Dorothee Wernicke, Hannah Ungar-Waron, and Myron E. Essex. “Suppression of the Humoral Antibody Response in Natural Retrovirus Infections.” Science 220, no. 4599 (May 20, 1983): 858–59. doi:10.1126/science.6302837.
  • Essex, Myron, Mary Frances McLane, Tun-Hou Lee, L. Falk, C. W. Howe, J. I. Mullins, C. Cabradilla, and D. P. Francis. “Antibodies to Cell Membrane Antigens Associated with Human T-Cell Leukemia Virus in Patients with AIDS.” Science 220, no. 4599 (May 20, 1983): 859–62. doi:10.1126/science.6342136.
  • Gelmann, Edward P., M. Popovic, Mikulas, D. Blayney, Henry Masur, G. Sidhu, R. E. Stahl, and Robert C. Gallo. “Proviral DNA of a Retrovirus, Human T-Cell Leukemia Virus, in Two Patients with AIDS.” Science220, no. 4599 (May 20, 1983): 862–65. doi:10.1126/science.6601822.
  • Gallo, Robert C., Prem S. Sarin, Edward P. Gelmann, Marjorie Robert-Guroff, Marjorie, E. Richardson, Vaniambadi S. Kalyanaraman, D. Mann, et al. “Isolation of Human T-Cell Leukemia Virus in Acquired Immune Deficiency Syndrome (AIDS).” Science 220, no. 4599 (May 20, 1983): 865–67. doi:10.1126/science.6601823.
  • Barré-Sinoussi, Françoise, Jean-Claude Chermann, Françoise Rey, Marie-Thérèse Nugeyre, Sophie Chamaret, Jacqueline Gruest, Charles Dauguet, et al. “Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS).” Science 220, no. 4599 (May 20, 1983): 868–71. doi:10.1126/science.6189183.

13. Marx, Jean L. “Human T-Cell Leukemia Virus Linked to AIDS.” Science 220, no. 4599 (May 20, 1983): 806–9. doi:10.1126/science.6601821.

14. 4 papers from the Gallo lab on the viral etiology of AIDS:

  • Popovic, Mikulas, Mangalasseril G. Sarngadharan, Elizabeth Read, and Robert C. Gallo. “Detection, Isolation, and Continuous Production of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and Pre-AIDS.” Science 224, no. 4648 (May 4, 1984): 497–500. doi:10.1126/science.6200935.
  • Gallo, Robert C., Syed Zaki Salahuddin, Mikulas Popovic, Gene M. Shearer, M. Kaplan, Barton F. Haynes, Thomas J. Palker, et al. “Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDS.” Science 224, no. 4648 (May 4, 1984): 500–503. doi:10.1126/science.6200936.
  • Schupbach, J., Mikulas Popovic, R. V. Gilden, Matthew A. Gonda, Mangalasseril G. Sarngadharan, and Robert C. Gallo. “Serological Analysis of a Subgroup of Human T-Lymphotropic Retroviruses (HTLV-III) Associated with AIDS.” Science 224, no. 4648 (May 4, 1984): 503–5. doi:10.1126/science.6200937.
  • Sarngadharan, Mangalasseril G., Mikulas Popovic, L. Bruch, J. Schupbach, and Robert C. Gallo. “Antibodies Reactive with Human T-Lymphotropic Retroviruses (HTLV-III) in the Serum of Patients with AIDS.” Science224, no. 4648 (May 4, 1984): 506–8. doi:10.1126/science.6324345.

15. Identification of gp120:

  • Kitchen, L. W., Françis Barin, J. L. Sullivan, Mary Frances McLane, D. B. Brettler, P. H. Levine, and Myron Essex. “Aetiology of AIDS—Antibodies to Human T-Cell Leukaemia Virus (Type III) in Haemophiliacs.” Nature 312, no. 5992 (November 22, 1984): 367–69. doi:10.1038/312367a0.
  • Allan, Jonathan S., John E. Coligan, F. Barin, Françis, Mary Frances McLane, Joseph G. Sodroski, C. A. Rosen, W. A. Haseltine, Tun-Hou Lee, and M. Essex. “Major Glycoprotein Antigens That Induce Antibodies in AIDS Patients Are Encoded by HTLV-III.” Science 228, no. 4703 (May 31, 1985): 1091–94. doi:10.1126/science.2986290.

16. Discovery of simian immunodeficiency virus:

  • Kanki, Phyllis J., Mary Frances McLane, N. W. King, N. L. Letvin, Ronald D. Hunt, P. K. Sehgal, M. D. Daniel, Ronald C. Desrosiers, and Myron E. Essex. “Serologic Identification and Characterization of a Macaque T-Lymphotropic Retrovirus Closely Related to HTLV-III.” Science 228, no. 4704 (June 7, 1985): 1199–1201. doi:10.1126/science.3873705.
  • Daniel, M. D., N. L. Letvin, N. W. King, M. Kannagi, P. K. Sehgal, Ronald. D. Hunt, Phyllis J. Kanki, Myron E. Essex, and Ronald C. Desrosiers. “Isolation of T-Cell Tropic HTLV-III-like Retrovirus from Macaques.” Science 228, no. 4704 (June 7, 1985): 1201–4. doi:10.1126/science.3159089.

17. Kanki, Phyllis J., R. Kurth, W. Becker, G. Dreesman, Mary Frances Mclane, and Myron Essex. “Antibodies to Simian T-Lymphotropic Retrovirus Type III in African Green Monkeys and Recognition of STLV-III Viral Proteins by AIDS and Related Sera.” The Lancet 325, no. 8441 (June 8, 1985): 1330–32. doi:10.1016/S0140-6736(85)92818-1.

18. Discovery of HIV-2:

  • Barin, Françis, François Denis, Jonathan S. Allan, Souleymane M’Boup, Phyllis J. Kanki, Tun-Hou Lee, and Myron Essex. “Serological Evidence for Virus Related to Simian T-Lymphotropic Retrovirus III in Residents of West Africa.” The Lancet 326, no. 8469 (December 28, 1985): 1387–89. doi:10.1016/S0140-6736(85)92556-5.
  • Kanki, Phyllis J., Françis Barin, Souleymane M’Boup, Jonathan S. Allan, Jean Loup Romet-Lemonne, Richard Marlink, Mary Frances McLane, et al. “New Human T-Lymphotropic Retrovirus Related to Simian T-Lymphotropic Virus Type III (STLV-IIIAGM).” Science 232, no. 4747 (April 11, 1986): 238–43. doi:10.1126/science.3006256.

19. On this slide, Essex also writes: 

  • Later epidemiological studies showed that HIV-2 was less lethal: Marlink, Richard G., Phyllis J. Kanki, Ibou Thior, Karin Travers, Geoffrey Eisen, Tidiane Siby, Ibrahima Traore, et al. “Reduced Rate of Disease Development after HIV-2 Infection as Compared to HIV-1.” Science 265, no. 5178 (September 9, 1994): 1587–90. doi:10.1126/science.7915856.
  • …and less transmissible: Kanki, Phyllis J., K. U. Travers, Richard G. Marlink, Myron E. Essex, Souleymane M’Boup, A. Gueye-NDiaye, T. Siby, et al. “Slower Heterosexual Spread of HIV-2 than HIV-1.” The Lancet, Originally published as Volume 1, Issue 8903, 343, no. 8903 (April 16, 1994): 943–46. doi:10.1016/S0140-6736(94)90065-5.

20. Connor, Edward M., Rhoda S. Sperling, Richard Gelber, Pavel Kiselev, Gwendolyn Scott, Mary Jo O’Sullivan, Russell VanDyke, et al. “Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment.” New England Journal of Medicine 331, no. 18 (November 3, 1994): 1173–80. doi:10.1056/NEJM199411033311801.

21. Lallemant, Marc, Gonzague Jourdain, Sophie Le Coeur, Soyeon Kim, Suporn Koetsawang, Anne Marie Comeau, Wiput Phoolcharoen, Max Essex, Kenneth McIntosh, and Vicharn Vithayasai. “A Trial of Shortened Zidovudine Regimens to Prevent Mother-to-Child Transmission of Human Immunodeficiency Virus Type 1.” New England Journal of Medicine 343, no. 14 (October 5, 2000): 982–91. doi:10.1056/NEJM200010053431401.

22. Thior, Ibou, Shahin Lockman, Laura M. Smeaton, Roger L. Shapiro, Carolyn Wester, S. Jody Heymann, Peter B. Gilbert, et al. “Breastfeeding Plus Infant Zidovudine Prophylaxis for 6 Months vs Formula Feeding Plus Infant Zidovudine for 1 Month to Reduce Mother-to-Child HIV Transmission in Botswana: A Randomized Trial: The Mashi Study.” JAMA 296, no. 7 (August 16, 2006): 794–805. doi:10.1001/jama.296.7.794.

23. Shapiro, Roger L., M.D. Hughes, A. Ogwu, D. Kitch, S. Lockman, C. Moffat, J. Makhema, et al. “Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana.” New England Journal of Medicine 362, no. 24 (June 17, 2010): 2282–94. doi:10.1056/NEJMoa0907736.

24. Two of Mike Cohen’s papers on HPTN 052 and TasP:

  • Cohen, Myron S., Ying Q. Chen, Marybeth McCauley, Theresa Gamble, Mina C. Hosseinipour, Nagalingeswaran Kumarasamy, James G. Hakim, et al. “Prevention of HIV-1 Infection with Early Antiretroviral Therapy.” New England Journal of Medicine 365, no. 6 (August 11, 2011): 493–505. doi:10.1056/NEJMoa1105243.
  • Cohen, Myron S., Ying Q. Chen, Marybeth McCauley, Theresa Gamble, Mina C. Hosseinipour, Nagalingeswaran Kumarasamy, James G. Hakim, et al. “Antiretroviral Therapy for the Prevention of HIV-1 Transmission.” New England Journal of Medicine 375, no. 9 (September 1, 2016): 830–39. doi:10.1056/NEJMoa1600693.

25. Cohen, Jon. “HIV Treatment as Prevention.” Science 334, no. 6063 (December 23, 2011): 1628–1628. doi:10.1126/science.334.6063.1628.

26. Gaolathe, Tendani, Kathleen E. Wirth, Molly Pretorius Holme, Joseph Makhema, Sikhulile Moyo, Unoda Chakalisa, Etienne Kadima Yankinda, et al. “Botswana’s Progress Toward Achieving the 2020 UNAIDS 90–90–90 Antiretroviral Treatment and Virologic Suppression Goals: Results of a Population-Based Survey.” The Lancet HIV 3, no. 5 (May 2016): e221–30. doi:10.1016/S2352-3018(16)00037-0.

 

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