Page History

Flossie Wong-Staal: [00:00:00] Yes, okay, good. I also want to thank the organizers for including me in this very historic meeting. The other day, I was texting somebody and after I clicked send, I noticed that my name was autocorrected to “fossil.” I think it is very appropriate in view of this meeting, although, still very sobering. It's wonderful to see so many familiar [00:00:30] faces and also, especially my previous coworkers, Bob [Gallo], Beatrice [Hahn], Veffa [Franchini], and hopefully George [Shaw] later on.

When I first went to NIH, in the early 1970s, retroviruses were all the rage, not as human pathogens at that time, but as important tools in molecular biology and also [00:01:00] in animal models for the study of oncogenesis. I think very few scientists at the time, as you've heard, even believed that human retroviruses existed. Being from Bob's lab, we were clearly in the minority.

Cold Spring Harbor has always held an important place in our research careers, it is is the mecca for retrovirologists [00:01:30]. They had this annual RNA tumor virus meeting that you've heard about which I attended every year. I remember the meeting was held in May, right before the Memorial Day weekend, every year. When the human retroviruses session finally was established, it was always on the last day, right when people were ready to take off for the long [00:02:00] weekend. Mostly it was just the presenters and a few stragglers that were left. Of course, things changed rapidly right after HTLV-I. 

My assigned topic for today is the discovery of HIV transactivator genes. I would also like to take a few minutes to talk about a current project that I'm quite excited about, [00:02:30] which is related to cure research. That would be my contribution for the history and the future of HIV/AIDS research.

You've seen this slide many times. The simple retroviruses are, of course, very simple. Expression of all the viral proteins is regulated strictly by host cellular factors interacting with cis-acting [00:03:00] viral elements. The first glimpse we had of a complex human retrovirus was when [Mitsuaki] Yoshida (吉田光昭, b. 1939) sequenced the HTLV-I genome and noticed there was a 3’ open reading frame, which he termed X. (1, 2)

Subsequently, I think Joe Sodroski showed (in 1984) that the LTR (long terminal repeat)-linked CAT expression was much enhanced in virus infected cells, suggesting the presence [00:03:30] of a viral encoded transactivator. (3) Later, a number of groups show that that activity can be attributed to a sequence or gene in this pX region (situated between env and LTR). Of course, the complexity increases from that. When we come around to the HIVs, you see that the viruses have a lot more [00:04:00] more bells and whistles.

Now, I know my perspective on the early events surrounding the discovery of the HIV regulatory genes is naturally focused through the filter of the work from our own group. I was very blessed at NIH with a team of very talented and hardworking young scientists from all over the world, from Italy, Germany, England, Scotland, [00:04:30] India, Iran whatever. I think Bob was a world traveler, and instead of collecting souvenirs, he collected postdocs. I felt very much at home being a foreigner myself. I cannot emphasize enough that there were a lot of contributors to this early molecular dissection of HIV. Many labs were active. After all, we were confronted [00:05:00] with an enormously complex new virus which is responsible for a devastating global pandemic. I think, we had a lot of motivation to do as much as we can, as fast as we can.

In fact, I think in the first four years, I would say from 1984 to 1988, is the period of intense hectic activity [00:05:30] and intense competition. There was a lot of collaboration as well between groups, but there was also a lot of competition. Now, a number of key studies early on provided the essential tools to actually decipher the HIV genomes. Now I should continue with that. 

I think one of the fallout of [00:06:00] independent simultaneous discoveries is that everyone gives their own discovery a different name. I think you heard about the naming disagreement of the virus. I think it's a lot worse for the molecular biology because there were so many genes, and everybody has their own pet name for the genes. Here is when Cold Spring Harbor intervened again, there was a meeting set up to have all the [00:06:30] active players involved to meet and discuss the total data at that time, and to try to reach a consensus for the names used. They wanted a chairman, who is respected, obviously, but also impartial, and Harold Varmus stepped into that role.

From this meeting, we decided on a list of names for the various genes and after the meeting with buy-in [Luc] Montagnier (b. 1932, co-discoverer of HIV with Françoise-Barré-Sinoussi) and from [Mitsuaki] Yoshida. We have, across the Pacific and across the Atlantic, agreement. We finally settled on this list of names and communicated that to Nature. (4) Finally, we had an agreement at least for the names of the genes. 

Just continuing on the vein of competition: The first [00:07:30] key study that we did was the cloning of the virus. (5) Beatrice, George, and Sasha Arya were instrumental in this work. You see that we published this work in Nature in November 1984. Then a month later, Marc Alizon in Montagnier’s lab reported the cloning of their virus. (6) This theme [00:08:00] continues when you look at the next milestone which is the sequence of their complete genome. Here we published in January of 1985 in Nature, the complete nucleotide sequence of actually two clones from virus. (7) And Marc Alizon and Simon Wain-Hobson published their data [00:08:30] in Cell, also in January 1985. (8) Now, it's not just the scientists who are competing, the journals are still competing because the dates are so close.

Just out of curiosity, I look at the submission date of the papers. You see that our paper was submitted on November 29 and accepted December 14, while for the Cell paper from Wain-Hobson [00:09:00] they were submitted December 26 and there was no acceptance date, so I guess it was accepted immediately. So, I think for some reason Cell, probably found out about a paper and they didn't want to lose that Nature. 

Now another key finding that we had was the obtaining of molecular clone with biological activity. This was work mainly done by Mandy Fisher [00:09:30]. This clone, HXB2, was able to not only infect T cells, but it's also highly cytopathic for it. I agree with what Ron Desrosiers said last night. It is immensely useful to have a biologically active clone because now you can introduce any mutation in the coding sequence, or even noncoding sequence, and determine its relevance, not only in infection [00:10:00] but in its cytopathicity. And we've certainly utilized this clone extensively, and others as well I should say. 

Now, the nucleotide sequence revealed several open reading frames in addition to gag, pol, and env. One can ask the question, whether those are real genes or just  aberrant open reading frames by looking at peptides derived from them and see if they are recognized by [00:10:30] patient sera. Using this kind of approach four genes can be identified. The vif gene, the vpr gene, the vpu for HIV-1, and nef. And then the one asked the questions are these genes really important for virus infectivity by introducing mutations in the infectious clone? Surprisingly, they were not. That's why they were [00:11:00] dubbed “accessory genes” rather than essential genes. But that doesn't mean, of course, that they don't contribute to virus infectivity or cytopathicity. In fact, Mandy Fisher had shown that defects in the vif gene greatly compromise the virus in its transmissibility and infectivity. I think later on you'll hear the wonderful story about [00:11:30] how vif can disable a host defense mechanism. I think Mike Malim is going to present that. 

Now, interestingly, the essential genes tat and rev actually were not revealed by the nucleotide sequence, and that's because the coding sequences were discontiguous: they were brought together by splicing events and [00:12:00] they were not immediately obvious from the sequence information. Sasha Arya in the group looked at functional cDNA clones (DNA artificially synthesized from RNA using reverse transcriptase) and looked at the ability to transactivate the LTR-linked CAT genes. (9) I should mention that again, [Joseph G.] Sodroski was the first to show that there was a transactivator protein encoded by HIV, because, as in [00:12:30] HTLV-I, the LTR-CAT was much higher, has greater activity in virus-infected cells. (10)

However, by analogy to HTLV, it was expected that this gene was encoded in a 3’ prime region. That was not born out by functional analyses. So what Sasha did is using cDNA clones from infected cells [00:13:00] and map the activity, and it actually maps to a region immediately before the env gene which was previously thought to be non-coding—because it was pretty short, I guess. It was actually bringing together two different exons.

I know that Andy [Rice] following me is going to give a detailed talk on the mechanism of tat transactivation [00:13:30] so I won't be labor it's mechanism, but just to say that not only is the localization of the gene different from HTLV tax, but mechanistically it's also very different because it's not a transcriptional activator-like tax. Instead, it functions post-transcriptionally as an anti-terminator.

Now the discovery of rev is somewhat serendipitous. Mandy [Fisher] [00:14:00] had shown early on that deletions or mutations in the tat gene completely knocked out infectivity. (11) Mark Feinberg in the lab then did further mutagenesis studies and he hit upon two very interesting mutants shown here, M1 and M2. (12) Both of these mutations were made within the tat gene, but one of the [00:14:30] mutants M1, has greatly reduced tat function but not completely and other mutant M2 actually has full tat function, and yet, both are completely replication-defective, suggesting that these two mutations may hit a gene that is separate from tat. If you look at the expression pattern by Northern blot [00:15:00] in wild type infected cells, you see three major size distributions. Genomic size RNA 9.2 kb, and then multiple, well, diffuse band at 4.3 kb and even broader band around 2 kb. Interestingly these two mutants show predominantly only the small molecular weight species. So somehow this novel gene [00:15:30] and is affecting the expression or the detection of the higher molecular weight RNAs. 

When you look at the corresponding cDNA clones, you see a very complex pattern, and this is only a partial list of all the possible splice donor acceptor utilization. [00:16:00] All of them actually utilizes the same major five-prime donor site and the same 3’ polyadenylation signal sequence so that it can serve on both ends, but internally there are all kinds of different splice acceptor donors utilized.

In general, there's the genomic RNA, which can serve as new packaged virus RNA genomes as well as mRNA [00:16:30] for gag-pol expression is the 9 kb species. The 4 kb species is very heterogeneous, encoding for the envelope and many of the structural proteins. In this mote, the small RNA and codes for tat, rev and nef.

You see that an interesting feature is that the higher molecular weight species, the 4 kb and 9 kb, all contain functional intronic sequences, which is removed in this 2KB species. Within this in intron sequence in the env region [an element is present] which is responsive to the novel gene protein rev. 

I think at this point, [00:17:30] a lot of groups joined in to analyze the function of Rev. Again, of course, Joe [Sodroski] and [Bill] Haseltine, who also discovered the rev genes shortly—I mean around the same time as we did. Bryan Cullen’s (b. 1951) lab, Warner Green's lab, [unintelligible 00:17:53] lab. Many, many others I can't possibly name them all. But the picture that emerges is [00:18:00] that the Rev protein is actually a shadow protein. It contains a nuclear export sequence, which interacts with export cellular factors and a nuclear localization signal, which interact with nuclear input factors. But in this region, there's also an arginine rich domain, which binds directly to RRE (HIV-1 Rev response element).

[00:18:30] What you have is that the Rev, while in the nucleus, can bind to incompletely spliced RNA, which contains the RRE. Now, normally cellular RNA that contains functional introns will either be retained and get completely spliced or degraded. They don't get outside to the cytoplasm, but of course the retroviruses have this problem because they do need to [00:19:00] have the genomic RNA, as well as the envelope RNA, and other, not fully-spliced RNA, translated in the cytoplasm. The Rev actually overcomes this dilemma by ferrying those high molecular weight species RNA out to the cytoplasm. The Rev protein of course, can recycle back into the nucleus and [00:19:30] do this all over again.

Now, one consequence of Rev dependence is that HIV infection is now actually divided into two phases. The early after-infection, when there's no Rev or low Rev, only the completely spliced RNA  would get out, but as Rev builds up, then you start exporting the Rev-containing [00:20:00] mRNA, and then virus production can happen.

Now, it's been proposed that insufficient Rev function can also contribute to cellular latency. With the current focus on the latent reservoir, I think it may reemphasize the role of rev—and tat, for that matter—in the maintenance of persistent viral [00:20:30] reservoirs. 

Now, I should also mention that, just for the record, Bob mentioned that the rex gene of HTLV predicts the rev gene of HIV, and that's not true. I mean, it may predict the presence of extra coding sequences but the function of rev was actually determined several years—I think a couple of years before the rex gene function [00:21:00] was analyzed. But it still amazes me to this day that two viruses of such different lineages would evolve almost identical mechanisms for overcoming this nuclear retention problem.

Now, you may ask, How do the simple retroviruses do that, because they don't have a Rev? And yet they have the same problem of exporting genomic and envelope coding RNA. [00:21:30] In that case, it's now known that they have cis-acting elements that constitutively transport the RNA. So I think tat and rev certainly are mechanistically fascinating, and as well as the other accessory proteins, and they've really drawn the curtain on many important cellular processes, including nuclear transport, [00:22:00] splicing, cell host-virus interactions, as in the APOBEC story and many, many others. 

But ironically, even though tat and rev are known to be essential for HIV, they have not been fruitful targets for antiviral therapy. I think as you know, the most effective therapy is targeted [00:22:30] against the viral enzyme so far, and they have essentially rendered AIDS into a chronic disease, at least in developed countries. Currently, there's really no clear path for strategies to utilize tat and rev as targets, but maybe in future, there will be, especially now with such intense focus on so-called cure research [00:23:00].

Enough of the history, I want to look forward to the future. As I said this is a project I'm quite excited about that has something related to cure research. Now I think there's a general consensus that the major goal for future AIDS research is towards a cure, is [00:23:30] working towards a cure. There are a number of strategies that's been tossed around, and I think it's clear that it has to be multi-pronged. It’s not sufficient to just block virus transmission or infection, and it's not enough to just reactivate latent viruses because then you receive the reservoir very efficiently and ideally one should also enlist the [00:24:00] host immune response to kill the virus-infected cells. 

The molecule I'm going to talk about is developed, is an antibody, a humanized monoclonal antibody against CD4. It's an antibody developed at UBI, United Biomedical Inc. which is headquartered [00:24:30] here in—we are very close to here in New York, Long Island and the founder of UBI is my friend and long-term collaborator, Dr. Chang Yi Wang. I actually met Chang Yi at the (second) international AIDS conference in Paris in 1985. It's a long time ago. I think everything now is in decades not in years. [00:25:00] I think inhibiting virus entry is a very appealing approach because you can stop the virus infection right from the start. And there has been a lot of efforts trying to block virus entry. From the antibody perspective, I think most of the efforts has been on neutralizing antibodies against gp120, either man-made or naturally occurring in patients. So far I think some very potent and interesting antibodies have been [00:25:30] found, but so far, I think the major problem is that none of them is really 100% broadly active, and as a single agent they're not able to avoid generating resistance. Now, one can, of course, also target the cellular receptors but that's no guarantee that you avoid resistance. There's another CD4 antibody TMB-355 which has been in the [00:26:00] clinic, by the way, and you can see virus rebound, I think within days after your dose in patients. 

UB-421 is a competitive inhibitor, and it's been shown to inhibit 100% of a broad spectrum of either tissue culture or wild clinical isolates. This antibody actually has been [00:26:30] tested by Tae-Wook Chun and Tony Fauci’s lab and he was actually very impressed. He said that's the best antibody he's ever seen. Now, UB-421 has clinical proof of concept. It's gone through preclinical but also phase 1 and 2A, phase 2A data, and show that, again, there's no virus rebound when dosed in patients. I'm [00:27:00] going to skip all that because of time and go to the latest phase 2 data results which I think is really interesting. This is a HAART replacement trial. Essentially, you have HAART stabilized patients, in which you withdraw HAART, and then dose the patients in two cohorts. One is [dosed] weekly for eight weeks, or bi-weekly [00:27:30] at 25 or a higher dose for 16 weeks and then they are put back on HAART. This trial was carried out at three different sites in Taiwan. The idea is to look at the patients to see if there's virus rebound and if there is, how long it takes.

What is very interesting is that you see that the patients at the start of the trial had negligible [00:28:00] viral RNA expression and this persisted throughout the duration of treatment with UB-421, and maintain, of course, when you put them back on HAART. Now, this, actually, has not been seen before as a monotherapy. If you compare to historical data, none of the drugs on the market would give you long, durable [00:28:30] viruses suppression. This (VRC01) is supposed to be a very potent neutralizing gp120 antibody. Likewise, you get virus rebound very, very early. Pro140 is a CCR5 antibody and that's doing much better. You see it but still, it doesn't persist beyond for very long. But UB-421, it really [00:29:00] persisted with the suppression at least up to the 16 weeks that we looked at. 

I think it's clear that UB-41 is a very ineffective virus inhibitor, but it seems to do more than that. It goes beyond that. The most interesting feature so far is that the treated patients seem to have a significant reduction [00:29:30] in the T regulatory cells, and this is in both cohorts. Now, of course, the function of T regulatory cells is still not completely clear, but many studies have linked depletion or down regulation of Treg to increase immune response, especially viral-specific immune response as well as immune activation. We were very interested to see [00:30:00] one of the abstracts presented at the recent international AIDS conference in Durban by this group, which they use an agent that depletes Treg cells specifically in this so-called “elite controller resist macaques” (SIV-positive) and what they see, I think that we've been sort of reading the whole thing is that the Treg depletion actually resulted in both [00:30:30] reactivation of latent virus and the boost of CTL (cytotoxic T cell) response. (13)

Indeed, we saw in our own hands, features that are consistent with that. For example, we see increase in CD8 T cell population, and by the way, there's no decrease in CD4 so that removes the concern about using a CD4 antibody to some degree. It also increased in [00:31:00] HIV antigen-specific proliferative response of CD8 cells. Now, in terms of the activation of CD4s, this was the observation that via CD4 cross linking there was increased in TNF-alpha secretion, and also the examples of activation of HIV expression from latent cells and I think this particular experiment was again done by Tae-Wook in Fauci’s lab.

Finally, [00:31:30] there's some indication that maybe there isn't a reduction of HIV reservoir as measured by proviral DNA. This just shows some of the patients. In a few patients of course, the viral DNA burden was already quite low, sometimes beyond the limit of detection. But in a few patients that have higher viral DNA, you will actually see a reduction of that [00:32:00] in the treated patient which seems to be maintained after you put them back on HAART.

So I think that's very exciting. Here you have an agent that seems to impact on all the axes of a cure strategy. It certainly can block receding of the viral reservoir by preventing cell-cell as well as cell-free infection. It may immune reactivate the latent CD4 cells, and then it may increase the CD8 cell immunity. And also it seemed to lead to reduction in the virus reservoir. Now whether this antibody, perhaps in combination with a different regimen, with a HAART regimen, for example, will lead to a functional cure [00:33:00] remains to be seen.

I think what UB-421 is that it's an example of the next generation of antivirals that may play a role in our efforts towards a cure and I think a lot of other similar agents may appear and it would be interesting to see what unfolds in the coming years because after all, we're not just interested in the history of HIV, but to [00:33:30] borrow a very trite expression, we want to make HIV history.

[Applause]. 

Participant 2: [inaudible 00:33:43]

Flossie: Yes, Okay. The comparison of our antibody with David Ho's. I actually have a slide for that, but I didn't show because of time. [00:34:00] His antibody is recognizing a different domain on CD4. It's a non-competitive inhibitor. It doesn't inhibit 100% of all isolates, it's only like 80%. And when he dose that in patients as a single agent within days, you get virus rebounds, so it's very different.

Paul Bieniasz (Moderator): Just to keep us on time, just one more question.

Bob Gallo: Just want to make a point. You mentioned surprisingly that there's no inhibitor of tat, Flossie. [00:34:30] There wasn't any good approach, surprisingly, not a good approach to knock off tat. [Susana] Valente at Yale has a tat inhibitor, which gives the most remarkable long-term effects I've ever seen and one of the most exciting things in all of HIV therapy research. That's now—

Flossie: Is it in the clinic?

Bob: Yes. It's a specific tat inhibitor, multiple papers on it actually. The shock and kill, [00:35:00]well, there's at least some papers arising that actually increases the size of the reservoir.

Flossie: That's because of, you don’t block. [unintelligible 00:35:06] That's why you shock, kill, and block [crosstalk].

Bob: Maybe there's other reasons that it's not so great. Maybe there's also other T cells being activated.

Flossie: No, I think it's obvious if you don't prevent reinfection, of course.

Bob: No. It's nothing against this approach but long-term virus suppression maybe is a real functional cure, if you can make it long term and you don't need therapy anymore, which is the [00:35:30]direction you are going in.

Flossie: Well, our first goal is functional cure, but I think I agree with Mark Harrington, I think we should always set the goal higher.

Bob: For viral, yeah, well, it's an interesting debate. I think if you can just keep the virus suppressed forever more and you only need a drug once a year or twice a year, you're essentially cured. We live with a lot of organisms, including viruses. I think if you're going to talk about eradication, prove it with provirus analysis of every cell of the body after the person is [00:36:00] dead, and then that's going to take gene therapy I think.

Flossie: Yes. Well, that's our goal.

Bob: I agree.

[00:36:05] [END OF AUDIO] 

Citations

1. Seiki, Motoharu, Seisuke Hattori, Yoko Hirayama, and Mitsuaki Yoshida. “Human Adult T-Cell Leukemia Virus: Complete Nucleotide Sequence of the Provirus Genome Integrated in Leukemia Cell DNA.” Proceedings of the National Academy of Sciences 80, no. 12 (June 1, 1983): 3618–22. doi:10.1073/pnas.80.12.3618.
2. Yoshida, Mitsuaki. “Discovery of HTLV-1, the First Human Retrovirus, Its Unique Regulatory Mechanisms, and Insights into Pathogenesis.” Oncogene 24, no. 39 (September 2005): 5931–37. doi:10.1038/sj.onc.1208981.
3. Sodroski, Joseph G., Craig A. Rosen, and William A. Haseltine. “Trans-Acting Transcriptional Activation of the Long Terminal Repeat of Human T Lymphotropic Viruses in Infected Cells.” Science 225, no. 4660 (July 27, 1984): 381–85. doi:10.1126/science.6330891.
4. Gallo, Robert, Flossie Wong-Staal, Luc Montagnier, William A. Haseltine, and Mitsuaki Yoshida. “HIV/HTLV Gene Nomenclature.” Nature 333, no. 6173 (June 9, 1988): 504–504. doi:10.1038/333504a0.
5. Hahn, Beatrice H., George M. Shaw, Suresh K. Arya, Mikulas Popovic, Robert C. Gallo, and Flossie Wong-Staal. “Molecular Cloning and Characterization of the HTLV-III Virus Associated with AIDS.” Nature 312, no. 5990 (November 8, 1984): 166–69. doi:10.1038/312166a0.
6. Alizon, Marc, Pierre Sonigo, Françoise Barré-Sinoussi, Jean-Claude Chermann, Pierre Tiollais, Luc Montagnier, and Simon Wain-Hobson. “Molecular Cloning of Lymphadenopathy-Associated Virus.” Nature 312, no. 5996 (December 20, 1984): 757–60. doi:10.1038/312757a0.
7. Ratner, Lee, William Haseltine, Roberto Patarca, Kenneth J. Livak, Bruno Starcich, Steven F. Josephs, Ellen R. Doran, et al. “Complete Nucleotide Sequence of the AIDS Virus, HTLV-III.” Nature 313, no. 6000 (January 24, 1985): 277–84. doi:10.1038/313277a0.
8. Wain-Hobson, Simon, Pierre Sonigo, Olivier Danos, Stewart Cole, and Marc Alizon. “Nucleotide Sequence of the AIDS Virus, LAV.” Cell 40, no. 1 (January 1985): 9–17. doi:10.1016/0092-8674(85)90303-4.
9. Arya, Suresh K., Chan Guo, Steven F. Josephs, and Flossie Wong-Staal. “Trans-Activator Gene of Human T-Lymphotropic Virus Type III (HTLV-III).” Science 229, no. 4708 (July 5, 1985): 69–73. doi:10.1126/science.2990040.
10. Sodroski, Joseph G., Roberto Patarca, Craig A. Rosen, Flossie Wong-Staal, and William A. Haseltine. “Location of the Trans-Activating Region on the Genome of Human T-Cell Lymphotropic Virus Type III.” Science 229, no. 4708 (July 5, 1985): 74–77. doi:10.1126/science.2990041.
11. Fisher, Amanda G., Mark B. Feinberg, Steven F. Josephs, Mary E. Harper, Lisa M. Marselle, Gregory Reyes, Matthew A. Gonda, et al. “The Trans-Activator Gene of HTLV-III Is Essential for Virus Replication.” Nature 320, no. 6060 (March 27, 1986): 367–71. doi:10.1038/320367a0.
12. Feinberg, Mark B., Ruth F. Jarrett, Anna Aldovini, Robert C. Gallo, and Flossie Wong-Staal. “HTLV-III Expression and Production Involve Complex Regulation at the Levels of Splicing and Translation of Viral RNA.” Cell 46, no. 6 (September 12, 1986): 807–17. doi:10.1016/0092-8674(86)90062-0.
13. He, Tianyu, Egidio Brocca-Cofano, Benjamin B. Policicchio, Ranjit Sivanandham, Rajeev Gautam, Kevin D. Raehtz, Cuiling Xu, Ivona Pandrea, and Cristian Apetrei. “Cutting Edge: T Regulatory Cell Depletion Reactivates Latent Simian Immunodeficiency Virus (SIV) in Controller Macaques While Boosting SIV-Specific T Lymphocytes.” The Journal of Immunology 197, no. 12 (December 15, 2016): 4535–39. doi:10.4049/jimmunol.1601539.

Index

• 1.6 Harold Varmus — Animal Retroviruses and Cancer Research
• 2.3 Mark Harrington — The Importance of Activism to the US Response
• 2.4 Robert Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents & Preparation for the Future
• 2.5 Françoise Barré-Sinoussi — Discovery of HIV
• 4.1 Ronald Desrosiers — The Origin of SIVmac: Non-human Primate Models for HIV
• 4.3 Beatrice Hahn — Apes to Humans: The Origin of HIV
• 5.2 Joseph Sodroski — Primate Host-Specific Selection of Immunodeficiency Virus Gag and Env Proteins
• 5.3 Michael Malim — Discovery of APOBEC Restriction
• 5.5 Andrew Rice — Mechanism of tat Transactivation
• 8.2 David Ho — Unraveling of HIV Dynamics In Vivo
• 2nd International AIDS Conference, Paris, 1986
• 13th International AIDS Conference, Durban, 2000
• Alizon, Marc
• analogy
• Annual meeting on retroviruses, CSHL
• APOBEC
• Arya, Suresh K.
• CAT assay (chloramphenicol acetyltransferase)
• CCR5 (chemokine receptor type 5)
• cDNA clones, cDNA library
• Cell (journal)
• Chun, Tae-Wook
• clinical trials (phases of clinical research)
• cohort study
• Cold Spring Harbor Laboratory (CSHL)
• convergent evolution
• Cullen, Bryan R. (b. 1951)
• cure vs. remission of HIV/AIDS
• drug resistance
• env
• Feinberg, Mark B.
• Fisher, Amanda G.
• gag
• gene mapping
• Genes
• gp120
• Haseltine, William A. (b. 1944)
• highly active antiretroviral therapy (HAART), combination antiretroviral therapy (cART)
• HTLV (human T-lymphotropic virus)
• LTR (long terminal repeat)
• macaque, rhesus macaque
• mechanism
• models (model systems, model organisms, modeling)
• molecular cloning
• monoclonal antibody
• Montagnier, Luc (b. 1932)
• National Institutes of Health (NIH)
• Nature (journal)
• nef
• New York
• Northern blot
• nuclear export signal
• oncovirus
• pol
• provirus
• reading frame, open reading frame
• retrovirus classification, subfamilies, and genera
• rev
• Rev response element (RRE)
• rex
• RNA splicing
• scientific competition and collaboration
• Session 5: Molecular Biology of the Extraordinary Virus
• Session 7: Prospects for an HIV Vaccine
• Session 9: Public Event
• simultaneous discovery (multiple discovery)
• Taiwan
• tat
• tax
• TNF-α (tumor necrosis factor alpha, cachexin)
• transactivation
• United Biomedical, Inc.
• Valente, Susana
• vif
• viral reservoir, viral latency, disease reservoir
• vpr
• vpu
• Wain-Hobson, Simon
• Wang, Chang Yi (王長怡, b. 1951)
• Yale University, Yale School of Medicine
• Yoshida, Mitsuaki (吉田 光昭, b. 1939)