Identification of interferon-stimulated antiviral genes that contribute to the HIV-1 transmission bottleneck (360G-Wellcome-202416_Z_16_Z)

Identification of immune mechanisms of HIV-1 control at mucosal transmission sites is of importance to facilitate the development of strategies to block infection prior to systemic virus spread. My host lab have shown that HIV-1 transmitted founder viruses are relatively resistant to type I interferon (IFN)-mediated antiviral activity (as compared to viruses replicating in chronic infection), suggesting that type I IFNs make an important contribution to the HIV-1 transmission bottleneck. This project will contribute to ongoing work aiming to identify the IFN-stimulated antiviral genes that drive the IFN-resistance of founder viruses. My first aim will be to confirm preliminary results indicating that high concentrations of type II and III IFNs also inhibit HIV replication and that founder viruses are relatively resistant to their activity; and to test the effects of lower IFN concentrations. Findings from these experiments together with results from the lab’s microarray and qPCR-based analysis of common/differential gene up-regulation by high/low concentrations of type I, II and III IFNs will then be employed to identify genes to which founder viruses may be preferentially resistant. My second aim will be to use siRNA knockdown to test the role of 1-2 selected genes in founder virus IFN-resistance.