Treating HIV-infected elite controllers as a model of HIV remission
Hiroyu Hatano, University of California San Francisco
Thematic Priority Area: Therapeutic Strategies for HIV
Innovative, Developmental, Exploratory Award (IDEA)
Although highly active antiretroviral therapy (HAART) decreases HIV-associated mortality, it does not appear to completely restore health, for reasons that remain unclear. These limitations are particularly apparent among older HIV-infected adults, which is of great concern in California given the age of the epidemic. Perhaps the only way to fully address these limitations is to effectively eradicate HIV from infected persons. While complete eradication may never be feasible, a “functional”cure in which patients are able to maintain undetectable viral loads indefinitely in the absence of therapy may be possible. The best evidence for this is the existence of the so-called “elite” controllers, whom we define as individuals who are HIV-seropositive, with plasma HIV RNA levels below the level of conventional detection in the absence of treatment. Controllers may be conceptualized as a naturally occurring model of a functional cure (or “HIV remission”), and are ideal patients in which to study HIV persistence and the possibility of eradication.
In our proposed CHRP-funded pilot studies, we will seek to determine to what degree virus continues to replicate in controllers. We will also determine the potential clinical consequences of residual HIV replication, if such replication is present. To address these questions, we will administer HAART to a subset of well-characterized controllers. Our short-term objective is to demonstrate safety and feasibility. Our long-term objective is to initiate a series of studies in which we drive the host/virus relationship closer to one of eradication.
These broadly defined objectives will be addressed in two specific aims: (1) to characterize the dynamics of viral production in HIV-infected controllers; and (2) to prospectively treat 10 controllers with HAART (raltegravir, tenofovir/emtricitabine) for 6 months and study the effects of treatment on viral dynamics and the host inflammatory response. Our primary hypothesis is that viral replication is ongoing in untreated controllers, and that HAART will reduce this replication. Our secondary hypothesis is that levels of inflammation (which are driven by low level viral replication) will decrease with HAART.
We believe our data will be highly informative to the many groups now working on developing a “functional” cure. If the level of plasma viremia decreases with HAART in our controllers, then this would suggest ongoing low-level viral replication, and would imply that complete eradication of replication-competent virus is not necessary to achieve long-term viral control. On the other hand, if the level of plasma viremia does not decrease with treatment, it would suggest that controllers have successfully shut-down the virus, and that controllers have achieved true long-term “remission.” Future studies could then be aimed at defining the immunologic mechanisms responsible for this virologic control. Such efforts would contribute to the development of novel therapeutic strategies (e.g., therapeutic vaccines) and would also be informative for preventative vaccine research in which the goal is to decrease the viral load set-point in individuals who subsequently become infected.