Hide & Seek
Paul Volberding, MD, helps create synergy at the amfAR Institute for Cure Research
by Jeannie Wraight
The amfAR Institute for HIV Cure Research was launched on World AIDS Day 2015. With only a little over a year under its belt, the Institute’s work thus far in wading through the many questions to a greater understanding of viral reservoirs, the primary barrier to curing HIV, is quite impressive.
In last month’s edition of Destination: Cure, we reviewed a summary of some of the basic structure of the Institute and highlighted some of the presentations from the HIV Cure Summit. In this edition, I sat down with Paul Volberding, MD, Director of the Institute and discussed his role and some of the groundbreaking work being conducted by the Institute’s dedicated scientists and staff.
Jeannie Wraight: Dr. Volberding, can you briefly explain the structure of the amfAR Institute for HIV Cure Research and your role within it?
Paul Volberding, MD: Sure. The Institute is based in San Francisco and administratively within the AIDS Research Institute of which I’m the director. The investigators asked me to join them as the Director and Principal Investigator [PI] of the Institute because I have a long record of working in HIV and have some really great staff members to help me do this. We provide the home for the Institute here in the [UCSF] AIDS Research Institute, and as the PI, I’m responsible for managing the Institute, supervising the staff, the budget and making sure we’re on track. I work very closely with our lead investigators—four scientists and a scientist from amfAR itself, Rowena Johnston. The six of us function as a Board and make decisions regarding the direction of the Institute. My role in that is to be the quarterback and coach I guess.
The CURE acronym, which describes the barriers to an HIV cure, is said to be essentially the Institute’s outline for its research: Chart the location of reservoirs; Understand how reservoirs are established and persist; Record size of reservoirs; Eliminate reservoirs. What has been your main focus or interest?
I’m really involved in all of the research. My strength is in clinical investigation and translational research. I’m particularly interested in the clinical work we’re doing. We’re starting one clinical trial and we hope to do more. My main job in the Institute is to provide an umbrella over the whole Institute and support of the scientists regardless of the direction of their research. The CURE acronym, in part, was a useful device amfAR came up with to look at cure research from a number of perspectives. There’s quite a bit of overlap within that. Any good scientific team has a number of people who don’t just work on one area but collaborate and cross over and we’re certainly encouraging that in the Institute.
What would the clinical research look like? Where would the trials take place?
We’re starting, in collaboration with the University of Minnesota with amfAR’s support, to do a trial where people that are HIV-infected, on treatment and fully suppressed, would volunteer to intentionally stop their treatment. This is called an analytic treatment interruption, or ATI, and we watch them very closely to see how long it takes for the virus to come back. Along the way, we look at a variety of markers, including ones that we’re developing here to see if we could better predict how long it takes to rebound. We think that will give us insight into the nature of the reservoir and why it’s activating. And so again, that’s a trial that involves direct human volunteers and, in the future, we would hope as we develop more cure drugs that we will as quickly as possible bring those to trial as well.
Can you briefly describe our current understanding of viral reservoirs?
It’s a changing concept because we’re still learning about the reservoirs. There are many aspects we don’t understand. But basically, we know that the virus can hide in cells. It’s what we call a latently infected cell. The virus has a viral genome. The virus is taken into the genome of the cell itself which is characteristic of this type of virus. We think that these latently infected cells are the reservoir. The reservoir means basically a collection of cells that are latently infected. They’re probably located all over the body. We can occasionally find reservoir cells in the bloodstream but we think it’s mostly located in tissues, probably mostly in lymph nodes and in the gastrointestinal tract, which is basically a big, hollow lymph node. We don’t think the reservoir is in any one spot. We hope that the cells we find in the blood reflect the size of the reservoir in the whole body because we can’t sample tissues from everywhere in the body. We tend to rely on the blood or occasionally biopsies from the gut to give us a better sense of what’s happening in the reservoir with these latently infected cells.
It sounds like, from presentations at the symposium, that you found additional cells that we weren’t aware of that harbor latent virus?
There’s a lot of interest in finding what the nature of the cells in the reservoir is, and we are using some very sophisticated techniques that narrow [the search] down to very small subsets of the lymphoid cells that might harbor the virus and that’s important because, as we look at, especially, tissues of the reservoir, we want to look very specifically at those cells.
Have there been barriers the Institute’s researchers have encountered? Such as necessary assays that don’t yet exist?
Absolutely. In part, what we’re doing is basic science. We’re still trying to understand the reservoir and how we can interact with it. In part, our challenge is really an engineering one. How can we best find the reservoir cell and what kind of new technologies can we apply to look for those? We have some very creative scientists here in the amfAR Institute that are working very hard to develop some highly sophisticated new assays, new ways of looking at the cells.
Can you discuss the importance of the TLR data and what further research is currently being conducted?
Sure. TLR stands for toll-like receptors. These are chemicals on the surface of the cell or sometimes actually in the cell that are part of what we call the innate immune system, which is fundamentally important part of our protection. It’s the part of our immune system that is the first responder when a virus, bacteria, or a foreign substance is detected in the body. We think these receptors are very involved in looking out for viruses like HIV.
The idea is that if we can use the chemicals that stimulate this part of the immune system, we might be able to wake up some of these latently infected cells in the reservoir and without causing inflammation, which is a risk. If we could wake up some of these cells, then maybe we can possibly come back with another approach. For example, a therapeutic vaccine that might help the body kill those cells. So the whole goal with the TLR approach is to use the innate immune system to activate and eliminate the cells in the reservoir. It’s really a tall challenge, but we think this is a good first step in our Institute’s approach to cure research.
Are there any therapeutic vaccines specifically that you might be looking at?
That’s the question of the moment. We’ve made a lot of progress in our understanding of the TLR and we have access to a number of TLR agents, but we have to combine it with a therapeutic vaccine. We have access to some really interesting ones and we’re in final negotiations to decide which one to go with; we’re going to make that decision very soon. Then we would be able to start looking at combined therapy first in a primate model. We hope to be able to move into human trials as soon as possible because even the primate models are not exactly like HIV, so we’re eager to do human trials.
I know it’s unfair for me to ask for a time frame, but I’m going to anyway.
I think it’s a good question. We’re very close to having a vaccine [therapeutic] that we want to work with so we should be in at least primate studies this year.
Yeah, in part because there’s only so much you can do in the laboratory, in petri dishes—the immune system is so complicated that you really have to quickly go into animals and the best animal model for HIV in people is SHIV, a similar virus in monkeys. I think we can get there pretty quickly.
That’s pretty impressive; you guys move quick! Next question, what would you say is one of the major discoveries so far?
The TLR [research has] shown some real promise in other studies, especially [the studies performed] in monkeys. We’re finding that it’s actually pretty hard to show the same activity in the laboratory. I don’t know whether that’s going to be an important observation or not. If [TLRs] end up not working in people, it might, in retrospect, be a very important observation that we really could rely more on [for] work in the laboratory to look at other agents if we have to. We think that’s important. And the analytic treatment interruption study that I mentioned in people is also going to be very important to move us along in developing assays to really try to be more precise in quantitating the reservoirs. So, I think we’re really making some good progress.
We spoke a little about the tissue reservoirs already. Is there anything else you’d like to mention?
Well, one intriguing problem is you can’t easily ask people to give up their organs [jokingly said]. Even lymphoids are difficult, so we’re trying to develop techniques to image the reservoir in tissues using radioactive labels, for example. We’re using very sophisticated MRI scanning techniques so I think that will be an important breakthrough if we could begin to quantitate the tissue reservoir in living people without having to biopsy the tissue.
Is there anything else you’d like to add?
We’re very appreciative of the support we’re getting and we really do see this as a very direct partnership. As I mentioned, Rowena Johnston is on our Board; she participates in all our decisions. So, in this case the funder, amfAR, is really an active participant, not just writing the check. I think that’s really one of the most important parts of this project.
Well, I think what you’re doing is great. The way conventional research is done is so fragmented. This type of collaboration could really move things forward quicker.
Absolutely. We get together several times a week to share data; we all see the data as it happens and that’s our commitment, really—to not do this as a conventional academic but as a a task. We want to make progress in finding a cure and we think this is the best way to do it.
For more information, log on to: http://www.amfar.org/cure-research-institute/.
Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.