What are your research priorities right now?
In the last ten years, I've focused in on trying to understand the pathogenesis of drug resistance; focusing on the virus host interactions, and how reductions in viral fitness can lead to improved immunologic outcomes. We are still working on these issues, focusing on antigen-specific T-cell responses, HIV-specific T-cell immunity; T-cell activation; T-cell turnover; T-cell trafficking, and so forth. But in the past few years, it's become quite clear to us that we really can't fully understand how drug resistance and viral fitness impact outcome without a complete understanding of the normal response to HIV; and since there is no clear consensus on the immunologic correlates of virus control, and as there are no really validated standard assays to measure this stuff, we have become very interested in the study of untreated people.
In particular we became very interested in studying a rare subset of individuals who we think are completely controlling the virus due to their immune responses; we call them elite controllers. About two years ago we began to aggressively recruit these individuals who have no measurable virus in the absence of therapy. And so while we're all still focusing on drug resistance and viral fitness, we're devoting more and more time to characterizing these elite controllers, and we're doing this in collaboration with a number of investigators across the country.
Ultimately, what we'd like to do -- and what we're starting to do -- is to use lessons learned from this type of work to perform immune-based therapeutic studies. Our ultimate goals with those studies are to, one, confirm what we understand about pathogenesis; and two, to come up with novel strategies for individuals who really cannot respond to or don't want to go on therapy.
Have you seen research questions come up based on your direct involvement with the pressing clinical issues that people face?
Yes, it's a two-way street, right? The lab informs the clinic, and the clinic needs to inform the lab. One of the things that we're really becoming interested in is these individuals who have been on long-term therapy, with viral load undetectable for many years, but their T cells have remained well below normal, and there's a sense that accelerated atherosclerosis or other types of complications. We haven't confirmed that, but others have the same sense.
As a consequence, we are now using our cohort to support two lines of investigation: one, the impact of aging on the immune system; and two, the impact of abnormal persistent inflammatory responses in the face of suppressive therapy on cardiovascular function, and so forth.
So these types of observations definitely feed some of our pathogenesis work -- I think, actually, it's one of our strengths.
In terms of immune-based therapies, are there any particular approaches that you're excited about right now?
Yes, we're very interested in a lot of work that's being done regarding the critical role -- the absolute key role -- that CCR5 plays in pathogenesis. For example, monkey experiments by Guido Silvestri really suggest that CCR5 is key and genetics work by Sunil Ahuja suggest that CCR5 is key.
And then there are some recent clinical trials data with maraviroc, a CCR5 antagonist, suggesting that these drugs have an effect on the immune system independent of its effect on the virus. So we're very interested in CCR5 inhibition as an immune-based therapeutic.
And based on the work of Danny Douek and our colleagues regarding the loss of mucosal integrity in the gut and the potential impact on long-term outcomes, we are very interested in a series of toll-like receptor [TLR] antagonists.
And I keep my eye very closely on what's happening in rheumatoid arthritis and the various different autoimmune disorders, because there's a tremendous number of very focused biologics that can be used to manipulate the immune system in presumably a safe way; and I think that the people doing research on transplant biology and autoimmunity might actually be the ones to come up with the next great thing that can really push the field forward in HIV.
Do you think it might be time to have some kind of collaborative discussion between researchers in those two fields?
I would love to see some kind of connection between the very successful, NIH-funded, Immune Tolerance Network and pathogenesis-oriented clinical investigators in HIV. Actually, I think that the Immune Tolerance Network should be a model for the future for individuals trying to figure out [HIV] immunopathogenesis issues.
And I see that you're involved in the NA-ACCORD, the North American AIDS Cohort Collaboration on Research and Design.
Yes. I think one of the best ways to move the pathogenesis field forward is to access information regarding what's happening in the clinics worldwide, or at least in the United States and so forth. And NIH has done, I think, a very nice thing by funding this NA-ACCORD multi-cohort collaborative approach, which is now getting up and going; which essentially is going to try to link all the cohorts in the states. I think that these kinds of database can uncover trends, like early mortality or new cardiovascular events, which can be important for clinical management or public policy. But I also think they can be important for pathogenesis research.
Was that something that you had a sense was happening in your clinic before you saw results from the SMART study?
You know, we had a sense -- a growing sense -- before the SMART data came out that HIV itself is causing lots of the complications that we used to blame on treatment.
I've had this growing sense that HIV itself is causing progressive neurologic damage; loss of mental acuity; perhaps cardiovascular stuff; perhaps renal stuff. And in a large part, based on that, I am becoming a bigger and bigger fan of early therapy, and think that -- essentially -- everyone with HIV needs to be on meds unless there's a reason not to be. That's been my sense, because I do spend a fair amount of my time in the clinic.
And in terms of advocacy groups like Project Inform and TAG, are there specific things you think we can be doing that would be helpful?
I actually was at a Project Inform town hall meeting recently, and I went there to talk about the Merck integrase inhibitor, which I think is an incredibly effective, fairly potent drug; and it's going have a huge impact on my patients with drug resistance. So I figured we would talk for a couple of hours about integrase inhibitors.
But I wish certain people had been at that meeting, because it was just amazing. It was packed, and it was primarily people that had been on long-term therapy; and all people wanted to talk about were these issues which, at the end of the day, I'm somewhat optimistic that a cure might be feasible; and I'm happy that people are now willing to at least talk about it again. it seemed to me always came back to chronic inflammation -- joint pain, weight loss, persistently low CD4 T-cell counts, various complications, despite having an undetectable viral load.
It really wasn't a discussion about drug toxicity. It certainly wasn't a discussion about getting viral load undetectable. It was really about quality of life issues after being on therapy for 10 to 15 years. And it really struck me that, at the end of the day, there we were talking mainly about what sounded like inflammation-related, autoimmune-type symptoms.
I actually thought that was a great success because it linked, via Project Inform, investigators with this broad cross-section of individuals struggling with the disease, and my only regret was that people who fund this type of research were not there. You could see what the next series of research questions is going to be.
One question that often comes up is whether you're optimistic about the possibility of getting beyond antiretroviral therapy at some point; whether the body might be able to be persuaded to do a better job of controlling HIV.
I'm actually very optimistic but -- I gotta tell ya -- I'm a bit dubious about whether we're going to come up with an immune-based therapeutic that prevents disease progression such that people never need antiretroviral therapy. But I think we can delay it, and we can probably improve the immune system in people on therapy.
But I actually think that immunopathogenesis-oriented work and immune-based therapeutics will lead to a cure, and actually, we're really focused on these elite controllers as a potential first step in that direction.
You know, maybe I'm naive -- I don't understand the viral latency stuff as well as I probably should -- but I'm somewhat optimistic that a cure might be feasible; and I'm happy that people are now willing to at least talk about it again.
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