Characterization and Elimination of the HIV Reservoir

Abstract

The current HIV epidemic is highlighted by the remarkable success of combination anti-retroviral therapy (cART). Unfortunately, life-long and continuous cART is necessary for infected individuals due to persistent HIV infection and rebound viremia if cART is interrupted. The ability of HIV to establish a reservoir within long-lived cells is a major barrier to improving treatment and affording a cure. Here, I first describe our work to characterize the HIV reservoir within hematopoietic stem and progenitor cells (HSPCs) and determine the contribution of infected HSPCs to residual viremia in vivo. We found that HSPCs bear HIV proviral genomes in almost half of donors tested (24 of 43). Furthermore, we found that HSPC-derived proviral genomes are represented within residual plasma viral sequences about 3-fold more than proviruses derived peripheral blood and bone marrow mononuclear cells. We also discovered that HSPC-derived proviruses that were genetically identical to plasma virus are very often associated with expanded clonal HIV proviruses found in peripheral blood and bone marrow mononuclear cells. Additionally, we identified a signature deletion within proviral sequences derived from HSPCs and mature PBMCs and CD4+ T cells, providing evidence that HIV-infected HSPCs can propagate the HIV genome to progeny through differentiation. This study sheds light on the heterogeneity of the HIV reservoir and presents evidence in support of a novel pathway for the establishment and maintenance of persistent HIV in vivo. Finally, I describe our work investigating strategies to potently reverse HIV latency and induce reservoir elimination using histone deacetylase inhibitors (HDIs). We determined that class 1-selective HDIs are superior to pan-HDIs in their ability to act additively with the PKC agonist bryostatin-1 to reverse latency, induce potent viral outgrowth, and promote elimination of latently-infected cells. We also found that pan-HDIs suppress potent viral reactivation; an effect that is correlated with their unique inhibitory effects on important pro-viral cellular factors, NF-κB and Hsp90. This work will significantly inform future studies that will further characterize the heterogeneity of the in vivo HIV reservoir and develop clinically pragmatic and effective latency-reversing agents that may lead to improved HIV therapy aimed at reducing the burden of persistent viral infection and hopefully affording a cure.