We propose to comprehensively investigate how blockade of PD-1 in humans affects the layers of molecular regulation of the antiviral immune response, and how this impacts viral replication in situ. Collectively, we expect these data to dramatically enhance our understanding of the mechanism of αPD-1 mediated immune recovery that can be utilized not only for the design of pathogen-specific immunotherapy, but also to enable further improvements in the efficacy of immunotherapy in general.