Grant: Operating Grant - PA: HIV/AIDS Bridge Funding - Biomedical/Clinical Stream

AIDS is a slow degenerative disease of the immune and nervous systems resulting from HIV infection. Despite considerable progress made in our understanding of HIV infection, we still do not completely understand how the virus causes disease and how it persists in infected individuals despite a vigorous immune response and highly suppressive antiretroviral regimens. HIV Viral protein R (Vpr) is a virion-associated protein that is required for efficient infection of macrophages, a cell type that plays a major role in HIV persistence and pathogenesis. In addition, Vpr has the ability to arrest infected T lymphocytes at a specific step of the cell cycle (G2/M) presumably to promote escape from innate immunity. Interestingly, recent evidence from our laboratory suggests that Vpr biological activities are dependent on the recruitment of a host protein destruction complex. Preliminary results reveal that Vpr subverts this destruction complex to target a specific group of cellular proteins called class 1 histone deacetylases (HDACs), which are involved among other things in remodeling the nuclear chromatin and controlling gene expression. The overall goal of this research project will be to test the hypothesis that HIV Vpr mediates the degradation of type 1 HDACs to create a host cell environment that is favorable for viral replication, dissemination and immune evasion. First, we will characterize the architecture and composition of the HDAC-containing complex(es) targeted by Vpr. Second, we will define the mechanism underlying the degradation of HDACs by Vpr and examine its functional relevance for HIV replication and persistence. Lastly, we will identify host genes affected by Vpr-mediated reprogramming of histone acetylation and examine its impact on gene expression. Ultimately, the elucidation of the interaction between Vpr and host cells will lead to a heightened comprehension of HIV replication and persistence.