Tuesday, November 28, 2023
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Editor's Note:
For many years after the discovery of the virus, HIV disease was discussed as having a period of "latency." The seminal studies by David Ho, MD, Director and CEO of the Aaron Diamond AIDS Research Center, and the Irene Diamond Professor, Rockefeller University, New York, NY, and his colleagues revealed quite a different picture. For many patients, highly active antiretroviral therapy changed the course of their disease by suppressing HIV replication to levels not possible previously. This profound virologic suppression also allowed Dr. Ho and his colleagues to embark on a series of studies that revealed that HIV replication, as well as lymphocyte dynamics, were ongoing and active at all stages of HIV disease. On the basis of this information, Dr. Ho suggested that the best treatment for HIV would "hit early and hit hard." At HIV Management 2006: The New York Course, held May 5-6, 2006 in New York City, Mark Wainberg, PhD, Director, McGill University AIDS Centre, Jewish General Hospital, Professor of Medicine and Microbiology, McGill University, Montreal, Quebec, Canada, discussed with Dr. Ho the current understanding of HIV pathogenesis and implications for treatment.
Dr. Wainberg: Hi. My name is Dr. Mark Wainberg of the McGill University AIDS Center in Montreal, Quebec, Canada. On behalf of Medscape HIV/AIDS, I'm interviewing Dr. David Ho, who is the Irene Diamond Professor of Medicine at the Rockefeller University in New York and the long-standing Director of the Aaron Diamond AIDS Center. Dr. Ho, you've been in the forefront of this field for many, many years. Congratulations on all of your accomplishments.
Dr. Ho: Thank you, Dr. Wainberg. It's good to be here.
Dr. Wainberg: Let me begin with the question that relates to some of the work that you're best associated with over many years: T-cell turnover, the half-life of T cells in an HIV-infected individual, and the impact of antiretroviral therapy on all of the above.[1-10] How do you see the field progressing from now into the next decade?
Dr. Ho: I see that the fundamental science has taught us what the treatment principles are. What I see over the next few years is that we will have better and better medications at our disposal to treat infected persons, and these medications will hopefully be associated with fewer side effects and better control of HIV, and be much more convenient. Hopefully that will not result in too much of an increase in cost.
Dr. Wainberg: In your talk today, you made reference to the fact that the CD4+ cell reservoir is limited, and that in order to preserve it over as long a period as possible, we probably should think more and more about early initiation of therapy. At the same time, you pointed out that in the real world, there are compelling factors, such as cost and ease of dosing, and where people live in terms of the affordability of drugs. So what exactly does "earlier" mean? In the ideal world, would you treat someone the moment that you know that they're HIV-infected?
Dr. Ho: In the ideal world, when the drugs are convenient and associated with very few side effects, my approach would be to preserve the immunologic reserve as much as I can, because we have learned over the years as HIV replicates in an uncontrolled fashion, and it would deplete the CD4+ cell reserve at a very rapid rate. In the long haul this is not going to be good for that individual, even if the CD4+ cell count seemingly is quite stable. This is what we have learned, and therefore I would intervene. However, I'm a realist as well, and the drugs do have side effects. Some of the regimens are still complicated, and when you go to the developing countries, cost is a major issue. So the final decision would have to be based on a balance between the therapeutic principle on the one hand and the practical realities on the other. It comes down to individual patient decision, physician decision, and of course there are authorities who would weigh in on this matter in providing guidelines.
Dr. Wainberg: Dr. Ho, your lab has also been in the forefront of studies on T-cell trafficking -- the fact that the T-cell reservoir is not static even in an HIV-infected person. T cells are constantly migrating throughout the body, among different sanctuary sites. Certainly we've learned a lot about this field from studies on HIV drug resistance in which you've been pivotally involved. Could you elaborate on our understanding of trafficking and reservoirs, and do you see any breakthroughs coming in this area in the next several years?
Dr. Ho: T-cell trafficking or turnover is fairly clear now. The CD4+ T cells and CD8+ T cells, as a consequence of HIV infection, are turning over at a rate 6-7 times faster than in a normal person. This results in a constant drainage of the immunologic reservoir, and we'd like to stop this as soon as possible. We also have learned that as you treat with drugs and control the elements that are contributing to active replication of HIV, there's a reservoir of a subset of CD4+ cells that carry the virus in a quiescent fashion. This pool of cells, although quite small, is very hard to get rid of; it has a long half-life. There's still a lot of controversy about the absolute half-life of that cell population. Is it a few months or is it several years? Of course that matters a lot because if it's several years, we will never get rid of it. If it's in the order of a few months to half a year, there's still the distinct possibility of eradicating it.
Of course, another obstacle is that I don't think that our drugs are completely effective. They may be 99.99% effective in controlling the viral load; however, there is still a little bit of replication going on in distinct cells. We also have to shut that down in order to achieve complete virologic control or HIV eradication.
Dr. Wainberg: Eradication is something that we all dream about, some of us perhaps in color. Now, you know, one of the great things about our field as it moves forward is that the drug companies seem to constantly be interested in bringing new drugs to market. We're really blessed by having lots of new investigational drugs that not only act against viruses that are resistant to existing classes, such as new protease inhibitors, with better resistance profiles, but there are also some agents coming forward that really work against novel targets that have not hitherto been developed in an efficient way. One of those, for example, is the Panacos maturation inhibitor, but the category that I really want to talk about now is the integrase inhibitors. Both Gilead and Merck seem to have promising new compounds, and do you think that there is any possibility at all that these drugs may lend themselves in some magic fashion toward eradication of HIV infection in a way that previous categories of compounds have not been able to do?
Dr. Ho: We could certainly dream about such a day when drugs would allow us to eradicate HIV. The integrase inhibitors no doubt will be a valuable contribution to our therapeutic arsenal. They are a new class of drugs, so that would be helpful to patients who are in need of so-called "salvage" therapy. However, I think that you were talking about the fact that these will prevent integration of the virus and therefore prevent the formation of the latent reservoir. It's certainly a theoretical possibility that will aid our eradication effort. However, I also try to temper that enthusiasm a bit because we've been at this game for a long time, and we haven't achieved the desired outcome. HIV infection is a cyclic process, and you could break this cycle anywhere. Right? In theory, if you block any step very well, you'll see a depletion or decay of the various pools.
In theory, if you administer integrase inhibitors quite early in the course of infection and limit the reservoir pool, then you will be off to a great start. Of course, you may also help to avoid the replenishment of the latent reservoir pool, and these 2 features may get more promising results than any typical reverse transcriptase inhibitor-protease inhibitor combination. We just simply need to do the experiment.
I spoke earlier of the little bit of residual replication that occurs in the presence of drugs. The other thing that I'm actually excited about is that it's a possibility that this residual replication is occurring because those cells have the ability to pump the drugs out, and therefore the effective concentration is too low. If you buy that theory, then it stands to reason to give an inhibitor that works on the outside of the cell. I actually would also be interested in looking at entry inhibitors that work on the surface and see whether that would aid the attempt to eliminate HIV.
Dr. Wainberg: I completely agree with you, and the last thing that either of us wants to do is give false hope to people who have HIV disease right now, but certainly we would agree that clinical trials are ultimately what will tell us the tale in regard to how well these drugs work. Maybe we will have great surprises. From my perspective, integrase inhibitors might much more efficiently impede the integrase step than any of the current drugs that also act at a preintegrational level, including the entry inhibitors. If that's so, it creates a rationale to test these ideas, and I don't doubt that your group will be in the forefront of exactly these kinds of studies.
Dr. Ho: Well, one of my colleagues is already investigating the protease inhibitors in patients, and what you suggest would be a logical follow-up at some point.
Dr. Wainberg: Let me turn to the subject of where the most important reservoirs of CD4+ cells that potentially can become infected actually reside within the body. One compartment that has received very little attention is the gut lymphocytes. We all know about Peyer's patches and the fact that the gut really represents a huge reservoir, some people say the largest reservoir of lymphoid tissue in the body. Why do you think we have not paid more attention to this particular reservoir than we have since the inception of antiretroviral therapy?
Dr. Ho: We have been recently informed by experiments done in monkeys, with SIV [simian immunodeficiency virus] infection, which initially showed that the gut is a very important site of virus replication and very important site of CD4+ T-cell depletion.[11] Those results sparked interest in doing similar studies looking at gut lymphocytes in humans,[12-14] but as you know, it's very hard to get material to do good studies. You would have to do endoscopy, and if you want to do the studies right, you have to do it not just once but multiple times. These procedures are sufficiently invasive and undesirable that they present major logistic challenges. Of course with the body of evidence recently pointing out its importance, I see more and more focus on it, and hopefully we could come up with noninvasive techniques to approach this problem.
Dr. Wainberg: I think that would really be important. In fact, some of my Canadian colleagues have data suggesting that going back to the early days of zidovudine monotherapy, some of the reverse transcriptase resistance mutations at positions 41, 70, and 215 lurk within gut lymphocytes. It's a very compelling argument that as we study chemotherapy in the future that we think about all reservoirs. I'm sure that the field will be looking at this issue very, very closely.
On another topic, since you have pointed out that the rate of decay may be 6 times faster in the context of HIV-infected people than healthy individuals, does that mean that we can translate that understanding into a recognition that for all of us, the immune system is aging along with the rest of our organs, and that if we live long enough, at some point we're all going to get immunosuppressed?
Dr. Ho: I think we have to worry about that, now that longevity is obviously increasing because of overall better healthcare. There's no doubt that in a person at age 70 or 80, the immune system is somewhat impaired. We know that from clinical profiles, and as you look at these studies, it's also clear that we only have a finite reserve. Sooner or later, that will run out, and HIV infection is simply speeding up that process by 6- to 7-fold.
Dr. Wainberg: That's a very novel perspective, so maybe one of the long-term benefits of truly successful research into HIV/AIDS will be to enable us to discover ways of maintaining immune function over long periods of time.
Dr. Ho: You're right. Over the past 4 or 5 decades, we learned a great deal about the immune system of a mouse, but it is through HIV that we are actually learning a great deal about the human immune system.
