D-104 Clonal proliferation of CD4 T cells encoding intact HIV-1

Abstract

HIV-1 causes a chronic, incurable disease due to CD4 T cells that contain replication-competent provirus but exhibit little or no active viral gene expression, and effectively resist combination antiretroviral therapy (cART). Such latently-infected CD4 T cells possess a remarkable long-term stability and typically persist life-long, for reasons that are not fully understood. We have used massive single-genome, near full-length next-generation sequencing of HIV-1 DNA derived from unfractionated PBMC, ex vivo-isolated CD4 T cells, and phenotypically complex memory CD4 T cells from peripheral blood and lymphoid tissues to characterize the dynamics and underlying mechanisms supporting viral persistence. These studies demonstrated multiple sets of independent, near full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4 T cells harboring intact HIV-1. Interestingly, we found that Th1 CD4 T cells, typically responsible for antiviral immune defense, seem to harbor the majority of such clonally-expanded intact proviruses in cells from peripheral blood. In addition, we noted that cells harboring clonally-expanded proviral sequences frequently expressed cell surface markers known to protect CD4 T cells during the vulnerable phase of clonal proliferation, suggesting that HIV-1-infected CD4 T cells rely on physiological mechanisms for maintaining viral reservoir stability through clonal expansion. A closer longitudinal analysis of intact proviruses in distinct CD4 T cell subsets in future studies will be highly informative for developing targeted interventions for viral reservoir manipulation in clinical settings.