The human genome has evolved a constellation of antiviral genes with the potential to target HIV. However, the efficacy of these antiviral proteins fluctuates dynamically in evolutionary terms; evolution of the viruses triggers evolution of host components and vice-versa. For instance, HIV has adapted to grow in human cells, in part, because it has adapted to escape human antiviral inhibition. In this project, the evolutionary signatures of past interactions of lentiviruses with their primate hosts will be used to guide functional and structural studies of HIV-host protein interactions. In particular, this project exploits genetic innovation at the host-virus interface, characterized by signatures of recurrent Darwinian selection, or positive selection. We use evolutionary signatures of such genetic innovation to derive “super restriction factors” that are more potent at inhibiting HIV and less susceptible to antagonism by viral proteins. By testing libraries of host restriction factors with random amino acid changes at the sites of positive selection, host proteins with novel properties can be derived. Finally, using the criterion of positive selection, a whole genome catalog will be created that will be used to prioritize candidate host proteins identified as part of genome-wide genetic screens or protein-protein interaction studies for further biochemical studies in other Projects in this application by providing a means of assessing if these interactions have been involved in past evolutionary conflicts with pathogens.