DESCRIPTION (provided by applicant): HIV-1 persists in patients despite years of suppressive treatment with antiretroviral therapy (ART) and results in disease relapse when treatment is interrupted. One major barrier to treatment eradication is a reservoir of latently infected CD4+ T-cells. Whether these latently infected cells give rise to low-level ongoing replication or episodically activate and produce virus is controversial but this viral persistence likely contributes to ongoing immuno-pathologic effects that include incomplete T-cell restoration and the global immune activation that are implicated in HIV associated cardiovascular, renal and hepatic disease even among those on highly active antiretroviral therapy (HAART). It has also been recently recognized that despite expressing some markers of T-cell activation, T-cells from HIV infected patients also exhibit markers of T-cell exhaustion or tolerance that may underlie the insufficiency of the immune response against HIV-1. Our work from the previous funding cycle suggests that the latent viral reservoir may be heterogeneous in composition in vivo and the molecular mechanisms underlying viral latency are likely complex. We find that both T-cells in the gut and those in the blood exhibit very low HIV expression levels despite high levels of T-cell activation. One unifying mechanism for the attenuated expression of HIV could be the T-cell exhaustion that appears to accompany HIV infection. Our preliminary data suggest that, paradoxically, after successful viral suppression on ART, the proportion of cells expressing CTLA-4, a marker of T-cell anergy, increases. In the current proposal we will investigate evolution of the cellular reservoir of virus from patients initiating therapy during chronic HIV infection by examining individual CD4 populations based on presence or absence of markers of activation and anergy. We will test the novel hypothesis that tolerance acquired as a byproduct of chronic HIV infection, attenuates viral expression and gives rise to the paradoxical retention of large numbers of cells with latent HIV infection during suppressive therapy. We will determine whether epigenetic modification of the HIV LTR coincides with epigenetic modification of promoters of genes associated with T-cell activation. Finally, we will examine the effects of agents designed to reactivate HIV from latency or that reverse T-cell anergy on virus expression from T-cells obtained from patients on suppressive therapy in order to form the foundation for future interventions to purge the latent reservoir. PUBLIC HEALTH RELEVANCE: HIV infects 40,000 US Veterans and despite the availability of potent antiviral drugs that inhibit HIV infection, small amounts of virus remain in all patients on treatment requiring lifelong therapy. This virus remnant and/or the drugs we use to treat it may also be contributing to increases in heart attacks, strokes, kidney and liver disease and increases in cancer. We need to better understand how HIV is able to hide in the body and what can be done to completely eliminate it. This proposed study will determine more exactly what cells are sheltering the virus and why they are able to do so. We will also test whether some new drugs are able to force HIV out of hiding from these cells. These studies might point to new interventions for ridding (eradicating) these persistently infected cells.

HIV infects 40,000 US Veterans and despite the availability of potent antiviral drugs that inhibit HIV infection, small amounts of virus remain in all patients on treatment requiring lifelong therapy. This virus remnant and/or the drugs we use to treat it may also be contributing to increases in heart attacks, strokes, kidney and liver disease and increases in cancer. We need to better understand how HIV is able to hide in the body and what can be done to completely eliminate it. This proposed study will determine more exactly what cells are sheltering the virus and why they are able to do so. We will also test whether some new drugs are able to force HIV out of hiding from these cells. These studies might point to new interventions for ridding (eradicating) these persistently infected cells.