Impact of Vpr-induced epigenetic remodeling on HIV persistence

IMPACT OF VPR-INDUCED EPIGENETIC REMODELING ON HIV PERSISTENCE ABSTRACT: HIV remains a significant problem worldwide, and despite advances in HIV therapies, a cure has yet to be discovered. A major barrier to virus eradication is the establishment of long-lived cell reservoirs that harbor latent provirus or that sustain chronic low-level virus production; therefore, achieving a cure will require a better understanding of reservoir formation and HIV persistence in these cell populations. While extensive effort has been directed at understanding reservoir formation in CD4+ T cells; much less is known regarding myeloid cell reservoirs. Thus, detailed mechanistic studies of factors that regulate HIV persistence in myeloid cells may reveal novel therapeutic targets that can be leveraged to eliminate this cell reservoir. One such factor is the HIV accessory protein Vpr, which is essential for pathogenesis in vivo and virus replication in myeloid cells, but not CD4+ T cells. However, Vpr’s primary function in myeloid cells remains enigmatic. This proposal will test the hypothesis that Vpr facilitates HIV persistence in myeloid cells by inducing epigenetic remodeling and chromatin opening at the integration site for sustained HIV transcription. Our preliminary studies support this model and indicate that epigenetic remodeling requires Vpr-triggered DNA damage repair signaling, which is a well-documented Vpr activity of unknown virologic function. The goals of this proposal are to characterize how Vpr remodels the nuclear environment and define its role in HIV persistence in macrophages through three specific aims, 1) characterize the functional impact of Vpr-directed epigenetic remodeling on the HIV promoter during acute infection and latency reactivation, 2) delineate the mechanism(s) of Vpr-induced epigenetic remodeling, and 3) comprehensively define Vpr-substrate interaction surfaces. Detailed mechanistic insights that reveal how Vpr reprograms the cellular environment are critical for understanding its role in HIV pathogenesis and have the potential to yield novel therapeutic targets that can be leveraged to diminish HIV pathogenesis in vivo, contributing to the long-term NIAID goal of virus eradication. 1