Mucosal infection with HIV-1 is characterized by the rapid induction of type 1 interferons (IFNs) at the initial sites of entry. However, the extent to which these cytokines control HIV-1 replication during the earliest stages of infection and their contribution to the transmission bottleneck are not understood. We recently found that transmitted founder (TF) viruses that have crossed the mucosa and initiated a productive systemic infection are significantly more resistant to the antiviral effects of type 1 IFNs than viruses that predominate during chronic HIV-1 infection. We also found that this heightened IFN resistance declines rapidly during the first 6 months of infection. To map the responsible viral determinants and IFN-stimulated genes, we have begun to generate infectious molecular clones of TF and matching 6-month consensus virus pairs and determined their IFN resistance profiles. Most recently, we have characterized HIV-1 transmission pairs, and found that antiviral genes up-regulated by type 1 IFNs during the earliest stages of infection exert significant selective pressure on the transmitted HIV-1 pool, resulting in the establishment of systemic infection by variants that are relatively IFN resistant. It will be important to determine whether these effector mechanisms can be exploited for the design of new prophylactic and therapeutic strategies to combat HIV-1.
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