Will a HIV Infection Cure Ever Be Achievable?
An interview of Steven Deeks, Department of Medicine, San Francisco General Hospital, University of California San Francisco, USA.
Steven G. Deeks, MD, is a professor of medicine in residence at the University of California, San Francisco (UCSF), and a faculty member in the Positive Health Program (AIDS Program) at San Francisco General Hospital. Dr. Deeks is a recognized expert in the immunopathogenesis of HIV. He currently directs a large research program dedicated to the investigation of the immunopathogenesis of antiretroviral-treated HIV infection. He kindly agreed to answer a couple of questions we had on HIV cure.
Alain Lafeuillade: Is chronic inflammation in patient virally suppressed by ART related to HIV reservoirs?
Steven Deeks: As been shown by our group and others, T cell activation and inflammation often persist in patients who are otherwise doing well on antiretroviral therapy. The mechanism for this persistent inflammatory state is not known. Since ongoing low-level viral replication seemed to be an obvious mechanism for inflammation, we performed a raltegravir intensification study and used blood and gut T cell activation as our primary outcome. To our surprise, we found that the addition of raltegravir to a stable regimen had no effect on any marker of inflammation, suggesting that low-level replication is unlikely to be a major factor in this process. Of course, this does not rule out an effect of viral production (rather than replication), but to date we have not seen much of a relationship between any measure of viral persistence and the frequency of activated CD38+HLA-DR+ T cells, although we have some emerging preliminary data indicating there may be an association if we look at other markers of T cell activation.
It should also be noted that in a prospective intensification study performed by Martinez-Picado and colleagues from Barcelona, a subset of treated individuals had evidence of reduced viral replication during raltegravir intensification; importantly, this subset also exhibited a sustained decrease in T cell activation. It is hence possible that viral replication may be a cause of T cell activation in some individuals.
Finally, work by Tae-Wook Chun and others suggest that HIV may be preferentially found in activated cells during therapy. This finding is not inconsistent with our more global findings in which we were mainly interested in determining the cause of T cell activation during therapy.
AL: What is the role of T cell proliferation and the size of HIV reservoirs?
SD: Although activated cells often proliferate and proliferating cells might be considered as activated, these processes are distinct. In contrast to our work in which focused on markers which are thought to reflect T cell activation (e.g., the co-expression of CD38 and HLA-DR), compelling work by Chomont and Sekaly suggest that homeostatic proliferation of certain T cell subsets might result in maintenance if not expansion of reservoir. In their experiments, T cell growth factors such as interleukin-7 appeared to cause proliferation without activation of latently infected cells. These data suggest that the nature of the reservoir may be very different in patients with low versus high CD4+ T cell counts since the pressures to maintain T cell homeostasis is presumably much greater in the former group. Indeed, in our own cohorts, we have found that the characteristics of persisting virus is very different in immunologic non-responders as compared to responders, with non-responders having much lower levels of cell-associated RNA.
AL: Can the immune system be manipulated to accelerate the clearance of the latent HIV reservoir?
SD: I believe that a combination of approaches will be needed in order to achieve a cure that is safe and scalable. In addition to efforts aimed activating transcription of latent HIV, we need to develop approaches aimed at enhancing the immune system’s capacity to identify and kill HIV infected cells. Along these lines, we have recently shown that an inverse correlation between the frequency of HIV-specific T cells in the gut and the size of the reservoir, which we interpret to mean that more effective T cell responses might contribute to the clearance of latent HIV. We are involved in an international network in which the efficacy of a therapeutic vaccine in reducing the size of the reservoir will be tested in prospective study.
AL: Can the latent HIV reservoir be purged therapeutically until the very last cell?
SD: This is a theoretical question for which no one can really provide anything but a guess. The experience with the so-called “Berlin patient” who had a bone marrow transplant suggests to me that not every infected cell has to be purged. This patient had evidence of residual HIV a few months after the transplant, yet the virus was not able to replicate effectively and eventually waned to where it was no longer detectable. Also, many believe that “elite” controllers represent a model for a cure and is absolutely clear to everyone that these individuals have large numbers of cells containing replication competent HIV.
AL: Is it time to begin ‘eradication trials’ in human or is there a lot to do in vitro and in animal models first?
SD: I am a strong advocate for moving drugs into clinical trials once there is sufficient pre-clinical data suggesting there might be some activity. This approach only applies to drugs which are reasonably safe, however. Drugs that have significant potential for toxicity should probably first be tested in animal models. The field should also realize that there will be many failures in the clinical trial arena. It will likely take years of trial and error in pilot phase I studies to identify a therapeutic strategy that can be moved in larger phase II studies.
AL: Are governments, funding agencies and pharmaceutical companies really committed in finding an HIV cure?
SD: I believe that the NIH is fully committed to curative research and that a number of pharmaceutical companies are developing a strong and sustained interest. The role of non-government funders such as amfAR and the IAS, as well as community-based groups such as TAG and Project Inform should not be taken for granted. These groups, along with this website’s organization, have been instrumental in pushing curative research to where it is now being perceived as a global research priority.
Key words: HIV cure, hiv inflammation, hiv persistence, hiv reservoirs