Cellular Identity of the Intact HIV Reservoir

ABSTRACT Persistence of the HIV reservoir is a major barrier to cure. Many cure-directed clinical trials use novel interventions to reactivate the reservoir for immune targeting and reservoir reduction. Improving the targeting and elimination of HIV reservoir requires a cell-by-cell understanding of where reservoir is and how reservoir persists after cure interventions. However, current strategies to identify the multi-modal biology of cells with integrated provirus are not able to fully resolve the intact proviral reservoir: they cannot detect provirus in closed chromatin and cannot discern intact from defective provirus. This proposal will work to interrogate cellular programs of the total intact reservoir using two new sequencing approaches to address the problems of proviral intactness and integration in closed chromatin. In aim 1, we will test the hypothesis that CD4+ T cells with provirus in closed chromatin are transcriptionally distinct from cells with provirus in open chromatin. In aim 2, we will test the hypothesis that cells with intact provirus have distinct transcriptional, epigenetic, and clonal features. We will therefore work to identify the distinct features of the intact reservoir and to generate a technical and analytic pipeline for adjunctive use across multiple cure strategies.