Evasion of innate immunity by HIV-1 during the early stages of viral replication

HIV-1 must avoid innate immunity in humans so that it can achieve successful transmission from one person to another.

We want to understand two aspects of these immune evasion strategies: how HIV-1 avoids a family of membrane proteins, known as IFITMs that block the entry of the virus into its target cell; and how it disables the early warning systems that detect invading viruses once inside. We have found that isolates of HIV-1 that represent those transmitted between people are inherently resistant to the activities IFITM proteins and this is a major contributor to their overall avoidance of innate immunity. We propose to understand how the transmitted viruses achieve IFITM-mediated inhibition. We will determine how IFITMs affect the entry process of the virus itself, the cell types it can replicate in and how antibody responses that arise in the first few months after infection lead to IFITM sensitivity. We will also study the role of a small viral protein, Vpr, that is associated with the HIV-1 particle. Our preliminary evidence indicates that Vpr shuts down the cell’s ability to detect virus infection and we will determine the mechanism by which it does so.

Studying these mechanisms will potentially yield new therapeutics to treat HIV and AIDS.