Paul E. Sax, MD: Can we cure HIV? That's the topic we're going to be discussing today in this Medscape HIV interview. My name is Dr. Paul Sax and I'm Clinical Director of the HIV Program at Brigham and Women's Hospital, Boston, and the Associate Professor of Medicine at Harvard Medical School.
Here with me today is one of my colleagues, Dr. Dan Kuritzkes, who is a professor at Harvard University and Harvard Medical School and also Director of AIDS Research.
So, Dan, let's look back to the 1990s when potent antiretroviral therapy was introduced. Dr. David Ho got a lot of attention because he said that if people were on these treatments for long enough then maybe they could be cured. What actually happened?
Daniel R. Kuritzkes, MD: I think David's observations were that if you gave potent therapy as you describe, you saw the rapid disappearance of virus from the plasma and from the blood, and if you monitored it carefully you could see that it [the virus] was decaying in different phases, each phase a little bit slower than the previous. The key insight that David had was that this decay, in addition to leading to removal of virus from the plasma, really reflected the death of infected cells.
So the idea was that if you could maintain treatment for long enough, eventually all the cells that were infected would die off. Unfortunately, what wasn't apparent from those early experiments; but later, what became clearer from the work of a number of groups is that you eventually get to a point where the cells just aren't decaying anymore. These are latent, quiescent cells that harbor HIV. They are not producing HIV most of the time, and therefore they don't die -- and it looks like they live about as long as we do.
Dr. Sax: So it was the discovery of the latent reservoir -- where are these cells?
Dr. Kuritzkes: That's one of the big questions in the field today -- exactly where are these cells? The cells are probably of several different kinds. We know that at least one population of them are the so-called resting memory CD4 cells. These are T-helper cells that have already been exposed to antigen, and instead of going on to fight some invading pathogen or foreign antigen, they have fallen back asleep, in essence. They are now quiescent or resting, but they have become infected with HIV and harbor the provirus in a latent form.
The virus is transcriptionally silent and no viral proteins are being made, so these cells are not recognized by the immune system and therefore don't get targeted for elimination by cytotoxic lymphocytes, for example. And because they're not turned on to make virus, they don't die.
The other population of cells is monocytes or macrophages which, of course, can be everywhere in the body and in different kinds: Kupffer cells in the liver, microglial cells in the brain, and macrophages in the lung. We really have a much less clear idea about the contribution of macrophages to persistence of virus than we do with lymphocytes.
Dr. Sax: So the practical issue is that regardless of where they're coming from or where they originate from, once HIV treatment is stopped the virus inevitably returns.
Dr. Kuritzkes: That's been the observation. One of David Ho's colleagues, Marty Markowitz, did studies[1] in which they took patients who were diagnosed soon after first acquiring HIV infection, often during acute HIV, treated them intensively with [as many as] 3 or 4 drug regimens, and then after a period of several years stopped their therapy. Almost uniformly, within a matter of weeks, there were signs of recrudescent virus replication.
Dr. Sax: It has come up again, this whole strategy of cure. It seemed to be quiet for a while but now it's gotten attention. What are some of the strategies that have been proposed?
Dr. Kuritzkes: I think the strategies boil down to a couple of different approaches. One is, is there some way of purging the reservoir? We have all these cells that are latently infected. What if you could activate them all under cover of potent antiretroviral therapy so that as virus comes out, it can't go anywhere, it doesn't propagate infection, and then the activated cells presumably would die or become targeted by the immune system and be destroyed, and then you'd be rid of HIV.
So that's an attractive idea, except the latent cells are a fraction of the total population of lymphocytes and monocytes, so you'd have to activate a whole lot of cells. And we know that immune activation can have really unwanted consequences.
Another alternative is to try the opposite approach. What if there were drugs or even gene therapy approaches that could silence the virus so it could never turn on again, sort of making the proviruses permanently transcriptionally silent? And then a third approach is through bone marrow transplantation.
Dr. Sax: Let me ask you about the second one. I've heard the phrase "functional cure." Is that what you're referring to?
Dr. Kuritzkes: That's right. So essentially it may never really be possible to prove that somebody's cured, because how could you prove that there's no virus hiding out?
Dr. Sax: Right.
Dr. Kuritzkes: But at least you'd be able to get somebody to a point where, without any antiretroviral therapy for some period of time, there was no evidence of viral replication, there was no evidence of disease progression, and -- equally important -- no evidence that they were at risk of transmitting virus to other people.
Dr. Sax: You mentioned bone marrow transplant. Tell us something about this remarkable case that was reported a couple of years ago.[2]
Dr. Kuritzkes: We know that most HIV, in order to enter cells, relies on the coreceptor (the CCR5 receptor) in order to be able to get into T cells and monocytes, in addition to its primary receptor, CD4. About 1% of Caucasians lack the CCR5 receptor and seem to be perfectly healthy people.
This one HIV-infected man had the misfortune of developing acute myelogenous leukemia, failed on chemotherapy for his leukemia, relapsed, and required bone marrow transplantation. [His physicians] were fortunate enough to be able to find a matched donor whose genetic composition was such that the donor lacked CCR5. The patient received the bone marrow transplant and then after the transplantation, it was a take, when they stopped the antiretroviral therapy --
Dr. Sax: That was pretty gutsy wasn't it, to stop therapy?
Dr. Kuritzkes: It was. In somebody who's just gone through chemotherapy and bone marrow transplant, to stop treatment is a bold move. But they did, and it turned out that the virus didn't come back. [Part of the issue was that the patient wasn't tolerating antiretroviral therapy in the peritransplant period.] This person actually wound up getting a second transplant because his leukemia wasn't doing so well, but again, no evidence of virus coming back. The last I heard, when updated over the summer in Vienna [XVIII International AIDS Conference, (AIDS 2010)], it's now 3 years since the initial transplantation without evidence [of any detectable HIV in the blood].
So I think the bulk of scientific evidence would argue that this is a functional cure.
Dr. Sax: Of course it wouldn't be practical on a large scale, but it does give one hope that some kind of cure is possible.
Dr. Kuritzkes: It at least says that this is within the realm of possibility, but not something you'd want to take a 10%-20% chance of mortality on.
Dr. Sax: Which brings us to the next question: If you were to place a bet, which are we going to see first: a practical cure for HIV, or an effective HIV vaccine that we can use globally to prevent the spread of the epidemic?
Dr. Kuritzkes: That's a tough challenge, to have to pick one or the other, because clearly the 2 major hurdles in the field are cure and preventive vaccine. I'm a little bit more hopeful about a vaccine than I am about a cure, just given the biology of retroviruses and the fact that there are lots of other persistent virus infections we have yet to cure. But I'm not a whole lot more hopeful.
Dr. Sax: This leads me to my last question, and it really has to do with why should we care so much about cure of HIV. People go on HIV therapy today and those who succeed are the rule, not the exception. The virus can be suppressed and it can be controlled. We now know that if people start early enough, their life expectancy can be comparable to that of people without HIV. So is it really so important to find a cure?
Dr. Kuritzkes: I think cure is still the Holy Grail. In the rest of infectious disease, we're used to curing, not just palliating or suppressing. There are accumulative toxicities of therapies, there's the constant worry of adherence and the consequences of nonadherence with drug resistance, and the obvious cost. If we knew that we could cure the infection and actually eliminate the infection, I think mankind would certainly be better off.
Dr. Sax: Yes; this is very interesting and a really fascinating topic, one for which I gather there now is research money available.
Dr. Kuritzkes: There is. In fact, the National Institute of Allergy and Infectious Diseases is now competing with a collaboratorium project which several groups are responding to in order to move the field forward.
Dr. Sax: Thanks very much, Dan. What we've been discussing is whether HIV can be cured. There is some very exciting research going on now and likely to be going on in the next few years.
Dr. Kuritzkes: Thanks very much. It's been a pleasure.
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Cite this: Paul E. Sax, Daniel R. Kuritzkes. Can We Ever Cure HIV? - Medscape - Oct 06, 2010.
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