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The Next Stage of HIV Eradication: Finding the Secret Reservoirs
A Discussion With Robert Siliciano, M.D., Ph.D.

February 8, 2009

There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet one of these impressive HIV researchers and read his explanation of a study he presented at CROI 2009. After his explanation, he then answers several questions from the audience.

Robert Siliciano: What I'm going to talk about today is a new way of looking at how well HAART [highly active antiretroviral therapy] works.1 As you know, in patients who are doing well on treatment, the viral load becomes undetectable. It's below the limit of detection of clinical assays. But with special assays developed by John Coffin and others, you can still see a small amount of free virus in the plasma. This is called residual viremia.

Robert Siliciano, M.D., Ph.D.
Robert Siliciano, M.D., Ph.D.

There's been a big argument in the field about whether this represents simply the release of virus from a stable reservoir, such as the one that our lab has been studying for a long time; or, alternatively, that it represents continuous replication of the virus that's occurring, because the drugs haven't really completely controlled replication. The latter scenario is clearly a disturbing one, because it raises a possibility of the evolution of resistance.

I'm going to argue that the residual viremia is due to release of the virus from stable reservoirs. We have directly analyzed the residual viremia. We don't see evidence for it evolving. What we do see, though, is that it seems to be coming from at least two different sources: this latent reservoir in T cells that we described a long time ago, and another -- as yet unidentified -- reservoir. And that is a disturbing result with regard to eradication.

But I think the optimistic thing is that we don't see evidence for ongoing replication. Really, the definitive experiment that people in the field have been proposing for a long time is to intensify therapy -- take a patient who is doing well on treatment and add a fourth drug, and see whether this trace amount of viremia goes down any more.

We have done this in collaboration with John Coffin and others, and it turns out that it doesn't. What this means is that we have already reached the theoretical limit of antiretroviral therapy. We will never reduce viremia any further using antiretroviral drugs, because this little bit of free virus that's in the plasma is not coming from new cycles of replication. It's actually coming from cells that were infected prior to therapy. And so, if we want to get rid of the virus, we have to deal with these stable reservoirs.


Watch video of Dr. Siliciano's talk (part 1 of 2)

The optimistic conclusion is that the drugs that we have now actually, in an adherent patient, completely stop the virus from replicating. A lot of people still have trouble with this idea, and most of the work I'm going to talk about today is actually a pharmacologic explanation of this idea. We think there is a missing dimension in the analysis of how well antiretroviral drugs work. It has to do with the steepness of the dose-response curve.

If you take that into account, what you find is that the drugs are actually way more effective than we thought they were. Just to give you an example: Some of the best protease inhibitors can produce a 10-log reduction in a single round of infection. That's a 10 billion-fold inhibition. This was not apparent before, because the assays weren't available to see this. But we think that by analyzing the inhibitory potential of antiretroviral drugs in the correct way, we'll be able to do a better job of choosing drug regimens, particularly in the case of patients who are failing therapy. By really knowing how much replication is occurring in the patient, and how much each drug actually inhibits replication or contributes to the inhibition of replication, we'll have a more rational approach to choosing drug therapy.

Reporter #1: Do you think, at the end of the day, that we should continue down the road towards the kind of eradication that you've described? Or whether we should really be promoting research in the basic sciences that look at ways in which we can physically get our bodies to coexist with the virus?

Robert Siliciano: I think we should be pursuing strategies for eradication. The first step in eradication is stopping the virus from replicating, and I would say that that step has been accomplished, as a result of the efforts of everybody who participated in the development of HAART. What remains, and which actually may prove much harder, is to find all of the stable reservoirs -- we know there are at least two -- and find ways to eliminate them. There is a lot of momentum now to try and do that.

Reporter #2: What are the implications of this for when to start therapy? Do reservoirs continue to be seeded over the course of active infection, and would it be better to start immediately?


Watch video of Dr. Siliciano's talk (part 2 of 2)

Robert Siliciano: That's a good question. When we looked in patients who were treated during acute infection -- during symptomatic primary HIV infection -- and then kept on HAART for a couple of years, the reservoirs were already established. It's possible that by catching people very, very quickly, we may reduce the size to some extent. And it's possible that delayed treatment may increase the size slightly. But I don't think that's really going to give us a way to attack the problem.

Reporter #3: Do you know what percentage [of residual viremia] comes from the known reservoirs and what percentage comes from the unknown reservoirs?

Robert Siliciano: In about half of the patients that we have analyzed, more than half of the residual viremia is coming from this alternative source. But in other patients, we don't see this. So we still have a lot of work to do. The problem is that it's extremely difficult to do these studies, because the number of viruses that are present in the blood of somebody who's doing well on treatment, at the average level, is about one virus particle per mL of plasma. So it's extraordinarily hard to collect these viruses and analyze them. The best I can say right now is that in about half of the patients, the residual viremia is dominated by this alternative source.

Reporter #4: I'm wondering if you have any clues about what the mystery reservoir might be.

Robert Siliciano: Our current hypothesis is that it represents infection of a progenitor cell in the monocyte/macrophage lineage, and then that cell proliferates after infection. When it does, it copies the viral genome, without any mutation, into multiple progeny cells that go off and produce the same identical virus. The reason I say this is because the unique characteristic of this predominant plasma population is that it's very oligoclonal, which is very unusual in HIV infection. HIV tends to diversify very dramatically, so finding an oligoclonal population is very unusual. One way to explain it is that it's being generated by cell division, which copies an integrated viral genome without error. But we don't actually know the cell source. We can't find any of the cells in the blood.

Reporter #2: Why is it that the virus doesn't continue to seed reservoir sites with ongoing replication?

Robert Siliciano: In patients on HAART? If there is ongoing replication in a patient who's not on treatment or who is failing therapy, there will be new sequences being deposited in these reservoirs. But the size of a latent reservoir in resting T cells is very small. It's one in a million cells. And it's not an efficient process by which these reservoirs are generated. When you have suppression of replication to below 50 copies/mL, there are just no new infection events, and the reservoir is not turning over anymore. You are just left with what you had when you started HAART.

There had been the idea that the reservoirs were being continuously replenished. We've directly looked at that, and we don't see that.

This transcript has been lightly edited for clarity.


Reference

  1. Siliciano R. New approaches for understanding and evaluating the efficacy of ARVs. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 16.

Additional Interviews With Dr. Siliciano:
CROI Interview
AIDS 2008 Interview
View Dr. Siliciano's CROI 2009 Presentation




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