Grant: Project Grant

Understanding host the immune system is exploited by HIV at the time of virus transmission is a major goal of the HIV research community. Foremost amongst these pathways is a family of molecules called type I interferons, which represent the canonical anti-viral immune response. One key cytokine in this pathway called IFNa2 was very strongly associated with increased (rather than decreased) HIV acquisition in a prospective cytokine analysis of a large South African clinical trial. This finding is contrary to data from monkeys, where short term application of interferons led to a decrease in SIV (the monkey version of HIV) susceptibility. A critical difference between these findings is the duration of interferon exposure, as chronic interferon expression is known to cause the immune system to downregulate its ability to respond to type I interferons, crippling this important defense. This proposal will test the hypothesis that prolonged expression of type I interferons in the female reproductive tract increase HIV risk by impairing HIV target cells in their ability to upregulate inteferon pathways, thus increasing their ability to support HIV replication at the time of HIV exposure in the mucosa. These findings could have important implications for understanding HIV transmission and risk profiling in clinical interventions.