Grant: Operating Grant

AIDS is a slow degenerative disease of the immune and nervous systems resulting from HIV-1 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 maintains itself in infected individuals in presence of a vigorous immune response and highly suppressive antiretroviral regimens. HIV-1 viral protein R (Vpr) is a virion-associated protein that is required for efficient infection of macrophages and dendritic cell, two cellular compartments that play 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) presumably to optimize viral replication. Interestingly, recent evidence from our laboratory suggests that Vpr biological activities are dependent on the association of the protein with a host protein destruction complex. The overall goal of this research project will be to test the hypothesis that HIV-1 Vpr binds a protein destruction complex to cause destruction of cellular proteins that may be part of antiviral defense systems. First, we will characterize the association of Vpr with the host protein destruction complex. Second, we will identify cellular proteins that are destroyed by Vpr to induce cell cycle arrest and to promote efficient infection of macrophages. Finally, we will investigate whether Vpr via its cell cycle arrest activity affects the function of cellular components of innate immunity. Ultimately, the elucidation of the interaction between HIV-1 Vpr and host target cells will lead to a heightened comprehension of viral replication and pathogenesis. Additionally, a greater understanding of host cell resistance factors restricting HIV replication may lead to the development of pharmacological agents that can boost their potency and thereby lead to treatments.