HIV/AIDS Research: Its History & Future Meeting
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Sharon Lewin: Thanks very much, Ashley [Haase]. Thanks to the organizers for inviting me. It's been an amazing few days. I feel honored to be here, particularly honored as the only Australian in the audience, except for one very important Australian, who I had the pleasure of meeting, Bruce Stillman, who's the Director of Cold Spring Harbor, who I hadn't met before.

I thought I would give you a little snapshot about—[00:00:30] it's mainly at the history of HIV. I want to talk a bit about the history of HIV in Australia, then give a personal story of how I got interested in cure research, talk a bit about the work we're doing, and then what I think might be needed in the future.

So, as opposed to—We've seen this slide a lot and what happened in 1981. (1) I wasn't in kindergarten like Dan Barouch, but I had only just started medical school [00:01:00] in Melbourne in 1981. I had been backpacking around the world the year before, just what every Australian does. HIV was not remotely on my agenda.

The first cases of aids were diagnosed in Sydney in April of 1982, and in Melbourne, in July of 1983. Anyone that's ever been to Australia knows there's this intense rivalry between Sydney and Melbourne, but Sydney did diagnose the first cases.

I really [00:01:30] became interested in HIV because as a young resident, I had done two years of work in a big teaching hospital in Melbourne. I went and worked in a mission hospital in the middle of nowhere in Kenya in 1989. Actually, at that time, HIV was enormously stigmatized. In fact, it was really difficult to even test patients at that time, but the growing reality of this being an epidemic of enormous [00:02:00] scale really hit me.

At that time, I returned back to Melbourne and completed my fellowship training in infectious diseases, and had always wanted to combine clinical medicine with research, which is what I went on to do.

September 2016, the state of HIV in Australia. We have 27,000 people living with HIV, which is absolutely nothing. It's about a third of the number of people living with HIV in New York City alone, and probably the burden of [00:02:30] one hospital in Durban. We have a thousand new infections a year. Again, tiny numbers, but these numbers haven't changed. Most of our epidemic is in men who have sex with men, hardly any HIV in people who inject drugs.

Sharon R. Lewin is a virologist and immunologist at the University of Melbourne and the Royal Melbourne Hospital


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#demographic cohort

#medical school, residency, and fellowship

#education and early career

#HIV/AIDS stigma

#lab vs. clinic

The reason why that HIV unfolded, it's a success story in many ways in Australia, was largely due to our Minister of Health, Neil Blewitt (b. 1933) in the early '80s. He was a minister for the Labor Government. [00:03:00] The Labor Government had just introduced Medicare or Universal Health Coverage. As someone that has worked in the public health system all my life, I can tell you that it really does work in Australia. Neal Blewett was also incredibly progressive. He was a big believer in listening to the science and for that, for the evidence to guide public health policy, which is why he introduced access to clean needles, actually, extremely early in the epidemic. He's largely driven by the science [00:03:30] and Alex Wodak who showed clean needles stop people from getting HIV, and started talking about that in the late '70s. Neal Blewett was also really fantastic with working with affected communities. On the lower right is Bill Bowtell, who was his main advisor at the time. Bill is a gay man and he managed to bring government and communities in very close discussion from the very beginnings of HIV. These [00:04:00] photographs actually come from a documentary that Staffan Hildebrand made of HIV in Australia. Staffan's here. I can't see if he's in the audience. Staffan’s here chronicling this meeting, but he did a documentary about HIV in Australia for the World AIDS Conference in 2014.

Added to what I think was fantastic, political leadership, fantastic partnerships with communities, we had a long history in Australia of real excellence in virology, [00:04:30] immunology, and clinical care. I think that also really shaped the epidemic from the beginning.

#community and patient participation

Ian Gust that many of you I'm sure will know, a well-known virologist who had worked for a long time in hepatitis B, very quickly adopted HIV testing in at-risk communities and blood banks. He was director of the Burnet Institute, where I did my PhD. He was directed from 1986 to 1992 when John Mills came to Australia. Again, I'm sure many of you know, [00:05:00] John was at San Francisco General for a long time. He was director of the Burnet from 1992 to 2002, made a very significant contribution with studies of the Sydney blood bank cohort who were infected with a nef-deleted virus.

I did my PhD actually with John and his partner, Suzanne Crowe. Suzanne was on the first investigators to show that HIV infected macrophages and one of the first investigators to show that drug resistance could develop to AZT. [00:05:30] I did my PhD after my fellowship training and I worked on HIV in alveolar macrophages. That set me up very well for studies in latency because working with macrophages is really hard. There's hardly any HIV there, even without treatment. I was well primed to set to work on latency in subsequent years.

We talked a lot earlier in this meeting about the science that was so important to make [00:06:00] us ready to respond when HIV hit in the early '80s. Although Peter Doherty (b. 1940) has never worked on HIV, I'd like to acknowledge Peter’s contribution who, of course, won a Nobel Prize with Rolf Zinkernagel (b. 1944) exactly 20 years ago, this month, in 1996, for identifying how cytotoxic T cells recognize altered self or MHC (major histocompatibility complex) restriction. I now actually lead an institute named after Peter, called the Doherty Institute. [00:06:30] It's a joint venture of the University of Melbourne, Royal Melbourne Hospital, has over 700 staff, all working on infection and immunity, the major focus on virology, immunology, and public health. We have the only BL4 facility in Australia. Peter is still active. He doesn't run a lab. He is very active in public debate around science and the need for evidence to guide public policy. He’s a fantastic scientific communicator and he writes a lot of books. One of them, [00:07:00] The Beginner's Guide to Winning the Nobel Prize, some of you might be interested in reading. (2) [laughter] Some of you here don't need to read it because you've already won one, especially—I actually really recommend it to anyone under the age of 35 because if you're over 35, I think it's unlikely it's going to happen, but Peter is really wonderful to be working with. It's a very exciting opportunity I have.

My interest in HIV latency [00:07:30] started in New York in November 1997. David [Ho] had just been on the front, the Time, Man of the Year. (3) And I'm so happy that no one has actually shown this in the whole meeting. I know that David's squirming in his seat there, but I was really hanging out to be the first person to show this photograph. I already lined up my postdoctoral fellowship with David I think two years before actually. I had a second child and then deferred coming to work with David. [00:08:00] In the meantime, he was Time Man of the Year, so it's a very hot postdoctoral fellowship to have and I loved every minute of it.

I arrived there with my husband, who's a lawyer, and our two boys, who were then very young. They’re now 23 and 20. We arrived two weeks after these famous publications that came out that had identified a reservoir for HIV patients on highly active antiretroviral therapy (HAART), the great work that Bob [Gallo] [00:08:30] described earlier, David had contributed as had Marty [Markowitz], Doug Richman, and others. (4)

My first role in the lab was to use what was then a sexy new way of quantifying virus using real-time PCR. (5) Actually, real-time PCR did really add an enormous amount in our ability to quantify virus persistence. I applied real-time PCR to the measurement of unspliced [00:09:00] and multiply-spliced RNA in these newly treated people on highly active antiretroviral therapy. What we found was that even people that were very well suppressed, there was persistence of this low-level, unspliced, cell-associated RNA. Interestingly, there was very little multiply-spliced RNA in these samples. And we actually struggled to understand what that cell-associated RNA means. I think we still are struggling with what that really means. [00:09:30] Is it low-level transcription? Is it virion stuck on the outside of the surface?

Actually, an answer to Paul's question, Sarah Palmer recently did some sequencing on some samples that we had in a clinical trial looking at defective virus, DNA, and RNA. You have a lot more G to A hypermutation in the cell-associated RNA. But it was proof that virus would persist on treatment. That work was done in close collaboration with Marty Markowitz. David has already mentioned [00:10:00] Marty, but he was a really crucial mentor to me. He really taught me that well-designed, small, but detailed clinical studies to really give some fantastic insights into pathogenesis. I've continued to use that model in my career subsequently.

I was involved in a really interesting paper to look at now on looking at the decay of the latent reservoir in individuals that were treated within six months of infection, with acute infection. (6) [00:10:30] In that paper, there's a lot of discussion about whether virus persistence was active or replication or latency. Using real-time PCR to measure DNA, we actually showed quite marked decay in HIV DNA and concluded that most of this was ongoing viral replication. This was stopped by ART which, in the end, was not really correct because we know that people treated acute infections still have ongoing persistent virus. [00:11:00]

David's lab was enormous at that time. There's David there on the left. David mentioned earlier that in the lab, there was a lot of people from Mainland China, really fantastic scientists that have all gone back to have major leadership roles across China. Linqi Zhang (张林琦), who's now at Tsinghua University, Zhiwei Chen (陳志偉) at Hong Kong University, Xia Jin (金侠) in the Institute Pasteur, Fujie Zhang (张福杰), who's not up there, but for years ran the antiretroviral [00:11:30] program for [Chinese] CDC. It's really been fantastic for me now being back in Australia where we work a lot in Asia to have these colleagues within China and ongoing, fantastic colleagues, and collaborators.

I also worked on immune reconstitution again, using real-time PCR to measure recent thymic emigrants. (7) That's been an ongoing interest of mine, other than cure, about what determines variability in immune reconstitution. (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) [00:12:00] This work is largely done now by Reena Rajasuriar, who is a PhD student with me from Malaysia. She's gone back to Kuala Lumpur, and now heads up one of the first clinical immunology labs in Kuala Lumpur.

When I got back to Melbourne, I was very interested in setting up models in vitro of HIV latency, because, as we've heard before, latently infected cells are so rare. They're hard to study and all the action [00:12:30] is over by the time we see people on antiretroviral therapy, latency has been established already. At the time, there were very few in vitro models of latency, and I thought this was really important for us to understand how it's established, how latency is maintained, and then, ultimately, how latency is reversed.

This was the dogma about infecting resting CD4 T cells. You heard that earlier from Bob [Siliciano] as well: that virus would enter a resting T cell, but doesn't integrate or [00:13:00] doesn't move into the nucleus very efficiently. I was very intrigued by studies from Ashley Haase back in the late '90s showing that, within days of infecting rhesus macaques who have lots of virus in non-proliferating Ki-67 negative cells. He wondered whether there was something unique about the tissue environment that would lead to direct infection of resting cells and establishment of latency. We showed that certain chemokines that are highly expressed in [00:13:30] lymphoid tissues such as CCL 19 and CCL 21, did actually facilitate the entry of the reverse transcriptase complex and allow for efficient integration. (20, 21, 22, 23) Similarly, if you have seen the link between dendritic cells, again, which you would expect to find in tissue, you can mimic and attain this phenotype of latency. (24, 25) And then, other groups including Bob's have shown that signaling just between endothelial cells and resting T cells will allow efficient entry and integration [00:14:00] of HIV. (26) 

 We've used these models to look at the very early events and establishment of latency, and then more recently in how latency is reversed. Most of that work has been done together with Paul Cameron. Paul actually did his postdoctoral fellowship with Ralph Steinman (1943–2011), who was the first person to show the importance of dendritic cells in HIV replication. Paul and I have worked together for over 20 years, and we co-head the lab still now. 

 We've used some of these models to now [00:14:30] look at molecules that could potentially reverse latency. Taking these latently infected resting primary T cells, treating them with various latency-reversing agents, and measuring virus production. When we first started working on HDAC (histone deacetylase) inhibitors in the mid-2000s following that paper that Bob mentioned, and which David had shown valproic acid potentially activated latency. At the time, we were working with a company [00:15:00] in Australia that was developing other HDAC inhibitors that were far more potent than valproic acid. They asked us to test these. This is metacept 1 and 3 and the derivatives of oxamflatin. (27) This has actually worked on a latently infected cell line. But we can see minimal virus production with valproic acid, but quite potent production of virus when we use these other HDAC inhibitors. 

 We became aware that there were many other HDAC inhibitors actually already in advanced clinical [00:15:30] development, one of them being SAHA vorinostat that, in fact, was already licensed in many countries for the treatment of cutaneous T cell lymphoma . (28) That shifted our interest from these compounds to ones that we knew were already safe in human studies. We then moved to test some of these agents in vivo. We did one of the first studies of vorinostat in individuals on antiretroviral therapies and strategy to activate [00:16:00] latent infection. (29) We started around the same time that David Margolis did a similar study using a single dose of vorinostat. We were able to use 14 days of vorinostat, something that the FDA was uncomfortable in approving here, but we have a different regulatory process in Australia.

We both found the same thing that vorinostat did in fact increase cell-associated on spliced RNA, didn't make much virus in the periphery and made no difference in the number of latently infected cells. [00:16:30] Similar findings were found with panobinostat. (30) And then more recently, we've looked at a far safer drug, high-dose disulfiram, again, showing that you could activate transcription. You could activate some virion production, but none of it led to elimination of latently infected cells, which is what we want to do. (31)

What's next? We're quite interested to work out if we can increase the potency of HDAC inhibitors. We've been looking at the activity of HDAC inhibitors ex vivo. (32) [00:17:00] Here, we're using HIV-infected CD4 T cells collected from HIV-infected individuals on ART. You can see that you can measure unspliced RNA with a range of HDAC inhibitors and the bromodomain inhibitor JQ1 as well as if you fully activate the cell.

If you look at multiply-spliced HIV RNA, you get virtually no splicing when you activate with an HDAC inhibitor. This isn't just because you're doing it in a resting T cell because actually in JQ1, and we've used a range of different models to [00:17:30] answer this question. You actually do get efficient splicing which seems to not happen with HDAC inhibitors.

There's many groups now that are showing that HDAC inhibitors may work very well in combination with other agents. (33, 34, 35, 36) HDAC inhibitors potentially are opening up chromatin to allow for transcription, but you need an additional stimulus to actually drive an enhanced transcription. Many groups have shown, including Bob and others, that HDAC inhibitors [00:18:00] synergies as methylation inhibitors, DNA methyltransferase inhibitors, bryostatin, disulfiram. It's actually the principle that Merck are currently using to identify new latency-reversing agents using a screening drug library in the background of low-dose panobinostat. I think, ultimately, we need to start trying to test some of these combinations in vivo  to see if we really can induce virion production. We're about to start a proof of [00:18:30] concept clinical trial of vorinostat and disulfiram early next year funded by Merck.

There are now some expanding options for latency reversal. Many epigenetic modifiers, the TLR agonists, specifically TLR7 agonists developed by Gilead look very promising. Activators of NF-κB, we've heard of bryostatin and also ingenol and other agents, many of which are now moving into clinical trials. 

Probably the biggest challenge though is that although [00:19:00] there seems to be many agents that shocked the virus, we really don't have anything that has shown to effectively kill or eliminate latently infected cells. Different strategies are being tested, enhanced immune-mediated killing, the T cell vaccines, broadly neutralizing antibodies, bispecific antibodies, antibodies that trigger ADCC may all be relevant, or alternative agents that will enhance apoptosis in the presence of HIV proteins such as BCL2 antagonist [00:19:30] may play a role.

Been quite excited by the recent work of broadly neutralizing antibodies in individuals on antiretroviral therapy. The first study published comes from Michel Nussenzweig looking at 3BNC117 administered while an individual is on ART, once they've stopped ART and then looking at time to var rebound. And they showed very nicely that depending on whether the individual received two or four infusions, [00:20:00] you could delay time to rebound potentially consistent with eliminating latently infected cells. (37)

Finally, the last few minutes, what are some of the major future challenges for HIV cure research? Well, I have to say that there are many people in the room that don't think latency reversal or shock and kill will work. I was delighted to see this from Bob Gallo who published just two days ago because we've had this debate before. (38) I do think we have to shock and kill with caution. Safety is absolutely paramount [00:20:30] here. Whether we can really shock all latent viruses is unclear. I do think that strategies to silence latent HIV permanently would be very attractive. We don't have any options there yet.

I do think tissue reservoirs are going to pose particular challenges. (39, 40, 41, 42, 43, 44, 45) There hasn't been much discussion about HIV infection of microglia in the brain. I do think in some individuals, HIV is certainly found in the brain. The gut may present particular [00:21:00] challenge. The recent work on alpha-4 beta-7 tells us that there is something very different happening in the gut. Of course, a lot of interest at the moment in lymph node with T-follicular helper cells being enriched for HIV on treatment. This may potentially not be latency. It may be compartmentalized reservoir of activated infected cells.

Finally, can late rebound be prevented or even predicted? Bob [Siliciano] mentioned that [00:21:30] this is evidence set of a long-lived latently infected cell and I agree with him that these individuals, particularly the Boston patients and the Mississippi baby, who had absolutely no detectable virus or DNA, and then months and years after rebounded. (46) We need much better tools to predict if rebound will occur or when it will occur and much better tools to manage it. That's really why I think we need the vaccine experts here because we need to generate some [00:22:00] form of long-term immunity that will be able to respond to any virions that are released.

One potential option other than vaccination is to take advantage of these advances in the cancer field around reversing T cell exhaustion with immune checkpoint blockade. The effects are really striking, particularly with combination immune checkpoint blockade. This is the progression-free survival of individuals, melanoma, who receive a single immune checkpoint blocker, [00:22:30] anti-CTLA-4 or combination immune checkpoint blockade. (47) You can see this combination immune checkpoint blockade, 50% disease-free survival going out years after treatment. We're currently looking at combination anti-PD1 and anti-CTLA-4 in macaques on ART together with Afam Okoye and Louis Picker. We'll be starting immune checkpoint blockade either alone or in combination in true studies that are occurring of people with HIV with malignancy. As John Mellors [00:23:00] has mentioned earlier, these compounds have been very difficult or actually impossible to get into people that don't have malignancy until we know a lot more about their safety and potentially their potency in affecting the reservoir. That work is funded by amfAR and DARE through NIH.

Finally, I think all of us are aware that a cure really is going to be of most relevance to low-income countries. In a high-income country like Australia, [00:23:30] there's absolutely no possibility that antiretroviral therapy will not be—will be available to everyone who needs it forever. But we don't have that confidence in the rest of the world. That's really why a cure, not only has to be effective but also needs to be pretty cheap.

#cohort study

 

Now, this was modeling work that I was involved. It is funded by the Bill and Melinda Gates Foundation and Andrew Phillips did the modeling. (48) He costed the costs of antiretroviral therapy and regular monitoring [00:24:00] in Zimbabwe and compared that to a cure intervention, that we could deliver after six months of antiretroviral therapy. It was a cure intervention that was 95% effective and after ART interruption, needed to monitor people every three months. 

He came to the conclusion that a cure intervention will be cost-effective if it's $1,400 or less. That's pretty cheap intervention and wouldn't cover something like gene therapy, for example. One of the [00:24:30] biggest costs in this model was the—The cost-effectiveness was dependent on the intervention, but also on the monitoring needed to ensure remission. If we're just going to be going for remission, we have to monitor people every three months. It may not be a cost-effective intervention than a true cure.

Finally, this is a history of HIV talk, and I wanted to end by acknowledging some of the fantastic women in HIV science [00:25:00] particularly several that have been fantastic mentors to me. Françoise [Barré-Sinoussi] , of course, doesn't need her name is listed here. She's a total inspiration to all of us, male and female. Suzanne Crowe, who was my supervisor as a PhD student remains a fantastic close colleague and friend. Brigitte Autran, who I spent my sabbatical within 2008, who actually really gave me the idea of starting to do clinical trials of HDAC inhibitors, many other women that are [00:25:30] here and others that have made major contributions to the HIV effort. Finally, acknowledging many of my collaborators and funders. Thanks very much.

[applause] 

Anchor
qa
qa

Ashley Haase (moderator): Bob, why not yet? You should respond.

Bob Gallo: One huge addition to the last slide is Flossie [Wong-Staal]. [00:26:00] You're too young. [chuckles]

Sharon: I haven't met Flossie but—

Bob: This perhaps should be more directed at my friend Warner Greene if he's still here. I don't know.

Sharon: He's at the back, I think.

Bob: Yes, because like receptors, I don't know in detail biologic characteristics, but I wondered if some of them, I suspect some of them are strong activators of T cells more broadly and hence, could be hazardous for promoting spread of small amounts of HIV release. So, maybe that should be Warner. [00:26:30] I don't think it's fair to you if I just mentioned it, but whoever knows?

Sharon: Yes. No. I can respond. Warner might be able to as well. Certainly, with the TLR7 agonists, you see quite—in monkeys, the studies are now being done in humans, so we only really know what's happening in monkeys on antiretroviral therapy. You see pretty impressive spikes of viremia after each administration. Similarly, you see very impressive spikes in CD-69 expression on CD4 and CD8 T cells, [00:27:00] which returns rapidly down to basal levels. What's different about using TLR7 agonist is latency-reversing agents, at least in these monkey models, is that there has been some decline in HIV DNA. They're very potent agents at shocking the virus. They probably have other adjuvant activities in clearing infected cells.

David Ho: Sharon, it's David in the front here. [chuckles]

Sharon: David, yes.

David: Let me [00:27:30] be a bit provocative and ask there's a lot of talk of shock and kill. I could see the need for latency reversal. But the killing component almost is said as equally important. But to me, a productively infected T cell has a lifespan of a day. If the drugs are on board to stop the spread, I'm a bit puzzled by the great emphasis on killing. [00:28:00] That's number one.

Number two, as you know, about 20 years ago, Alan [Perelson] and I struggled with the quantitative issues concerning the latent reservoir. You could only activate a certain percentage with each intervention, and that intervention is stopped by T cell activation. We know clinically if you have a few percent of your T cells activate simultaneously, you're going have a toxic shock-like syndrome. [00:28:30]

So how many interventions would be needed if—let's say, the reservoir is small, 10 to the 5, 10 to the 6, and you can only get rid of 3%, 5% at a given time, how many years is that going to take, unless you have a reversal agent that will do it simultaneously without activating the immune system?

Sharon: Yes. They're both excellent points. I think the focus on the need for [00:29:00] kill probably comes from some of Bob [Siliciano] work on in vitro stimulation with HDAC inhibitors, where you get virus production and the cells don't die. And then the clinical trials that you do get virus production and there's no decline in HIV DNA. But there may be a whole lot of reasons for that. It might be that we haven't given it—the drugs aren't potent enough. We haven't given it for long enough time. I think the jury's still out on that.

How many interventions over [00:29:30] what period of time? I don't know. I'm not sure whether we need to be every—Well, first of all, a large proponent of what we're measuring could be replication-defective. Some latently infected cells may be easier to activate than others. There's some evidence to suggest that that may be more transcriptionally active before you come in with an intervention. There's some people—I know Miles Davenport's variants in modeling that about—theoretical intervention, ideal thing to [00:30:00] model.

Ashley: It's an important back of the envelope, calculation. What you do, it's a formidable challenge. I think Paul's next.

Paul Bieniasz: How do you account for the apparent lack of splicing when you reactivate with the HDAC inhibitors?

Sharon: Yes. We've got a few thoughts around that. It could be with how HDAC inhibitors also tat function and tat acetylation itself. We're looking at a few—

Paul: But you need [00:30:30] splicing to get tat?

Sharon Yes. You're going to have some base of—You do produce virions with HDAC inhibitors. It's just that you reduce a tiny amount compared to what you do with mitogen activation. We know that from ex vivo work and also some of the clinical trials. There is some modest virus production, but you never get that amplified production.

Paul: But to produce a virus, you need [00:31:00] essentially normal splicing.

Sharon: You do need splicing, but it becomes an amplified response so that you've got the initial shuttling in of tat and rev and then the whole thing amplifies it—with more and more tat. That is where the blockage that you never really take off with efficient splicing. It's inefficient in these models.

David Gludish: Yes. One follow-up to David's point. I think the issue is that if you reactivate [00:31:30] just the virus without activating a T cell, the T cell doesn't proliferate. The reason the T cell dies in response to HIV infection has been worked out, and Vpr kills them, they die from cell cycle arrest, but if they're not proliferating, they're not cleared by cell death mechanisms. The same thing we have in macrophages. You don't—each of the infected macrophages don't die because they're not cycling. That could be one of the reasons that you see virus production without cytopathic effects.

The second question is maybe you [00:32:00] have looked or you know, but what's the strength of the expected immune response before latency reactivations to some of the patients that have been on, let's say, long term suppressive ARTs? You don't get much of a reduction of the reservoir, but what do we expect? What are the antibody titers? What's the T cell response prior to latency reactivations? Have we looked?

Sharon: Yes. People that are on long-term antiretroviral therapy with very little antigen and presentation, [00:32:30] you do get decay and reduction in numbers circulating CTLs. Then,  Bob and others have shown that you've got high level of CTL escapes. Whatever is there could work, even in the reservoir contains CTL escape mutations.

John Coffin: Yes. A concern that has arisen. We've been thinking about the clonal expansion of cells with non-defective proviruses in them is that something is driving that expansion, which means [00:33:00] that if you do a treatment that eliminates those cells or does not eliminate them completely, then whatever the force is that drove that expansion is still there and these cells will tend to come back again. If you don't get them out right away. You can't just, at least in theory, you may not be able to wait a little bit and treat again because they're tending to spring back because of whatever force it was that drove them to expand in the first place, [00:33:30] like antigen for example.

Sharon: Yes. I think the approach will be very different once this is really demonstrated that clonal expansion's a major driver, the driver for that, whether it's immune activation or antigen-specific responses or--

John: It's all of the above I think.

Sharon: Yes.

[00:33:49] [END OF VIDEO]


#cure vs. remission of HIV/AIDS

Citations

  1. Gottlieb, Michael S., Howard M. Schanker, Peng Thim Fan, Andrew Saxon, Joel D. Weisman, and I. Pozalski. “Pneumocystis Pneumonia—Los Angeles.” MMWR Morbidity and Mortality Weekly Report 30, no. 21 (June 5, 1981): 250–52.
  2. Doherty, Peter C. The Beginner’s Guide to Winning the Nobel Prize: A Life in Science. New York: Columbia University Press, 2006.
  3. “Time Man of the Year 1996: David Ho.” Time 148, no. 49 (December 30, 1996): 52–87, https://time.com/vault/issue/1996-12-30/page/1/
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