The role of IFITM-mediated restriction of HIV-1 entry in acute infection and viral tropism (360G-Wellcome-098049_B_12_A)

Human Immunodeficiency Viruses must avoid host innate and adaptive immune responses that restrict their replication in vivo. This is in part achieved through the action of several viral accessory gene products. The HIV-1 Vpu protein counteracts the antiviral activity of the interferon-induced membrane protein Tetherin, which inhibits the release of diverse enveloped viruses from infected cells. We will use virological, biochemical and microscopy-based studies to understand the molecular and cell ular basis of how Vpu and other viral proteins subvert the trafficking of tetherin to prevent its incorporation into assembling virions, and to identify and characterize the cellular proteins required for these processes. Tetherin is not the only target of HIV-1 Vpu. We have used isotope labelling of plasma membrane proteins to identify a novel Vpu target, TOV3, a glutamine transporter. TOV3 is essential for proliferation of activated CD4+ T-cells raising the possibility that Vpu modulates T-cel l function by limiting glutamine availability. We will determine how Vpu-mediated TOV3 targeting affects viral replication and proliferation/survival of infected T-cells and macrophages to understand how this activity might contribute to HIV-1 pathogenesis. We will also adapt the isotope labelling to identify further targets of HIV-1 Vpu and Nef in HIV-1 infected primary cells