Evasion of innate immunity by HIV-1 during the early stages of viral replication (360G-Wellcome-207442_Z_17_Z)

The entry process of HIV-1 and the early events of its replication cycle are vulnerable to interferon-induced restriction and pattern recognition. We have shown that a family of interferon-induced membrane proteins (IFITMs) restrict the entry of HIV-1 dependent on their CD4 and coreceptor usages. Importantly, viruses that are transmitted between individuals are able to avoid IFITM-mediated restriction, correlating with their inherent resistance to type-1 interferons. Therefore, IFITMs are an important barrier for person-to-person spread. In this proposal, we will identify the determinants of IFITM resistance/sensitivity in the HIV-1 envelope glycoprotein (env) and use this knowledge to answer outstanding questions about the cell biology of HIV-1 entry and tropism. We will characterize how escape from early antibody responses in patients leads to the emergence of interferon-sensitivity in env, and how a polymorphism in ifitm3 limits host control of HIV-1 replication in acute infection. Lastly, we will build on preliminary data to understand how the virion-associated accessory protein, Vpr, shuts-down pattern recognition receptor signalling immediately after cellular entry, and identify the host protein(s) it targets to achieve this. These studies will yield important insights into the avoidance of innate immunity by HIV-1 of relevance for therapeutic intervention and immunogen design.