Project Summary Viruses exploit cell surface receptors to gain access to the interior of host cells. These receptors are now appreciated as major obstacles to virus spillover, a process by which animal viruses move from one host species into another. In the many documented examples of spillover, viruses typically use the same entry receptor in the old and new host, but need to acquire mutations to make them compatible with the specific ortholog of that receptor found in the new host. Diverse viruses such as avian influenza viruses, rodent arenaviruses, MERS coronavirus, and possibly SARS and Ebola viruses all overcame receptor barriers in humans as they transmitted from their animal hosts. Here, we explore the following hypothesis of disease emergence: viruses can more easily overcome receptor barriers when host individuals of specific receptor genotypes come into contact. We use the simian immunodeficiency virus (SIV) reservoir in African primates as a model for this, and investigate the role that the SIV/HIV receptors, CD4 and CCR5, play in limiting spillover of these viruses. Primate lentiviruses (SIV/HIV) are an excellent model because the HIV/SIV receptors CD4 and CCR5 serve as significant host barriers to the spillover of these viruses between primate species. We and others have shown that (1) CD4 and CCR5 vary from one species to the next in their ability to serve as receptors for HIV/SIV, and (2) different individuals within primate populations have different virus susceptibilities because of receptor polymorphisms. We leverage genetic data and biomaterials from approximately 1,300 primates representing 15 different species, and a broad array of different HIV and SIV variants, to test the idea that certain individuals within populations are better poised to transmit or receive infection during spillover scenarios. The main innovation of the proposal is to define the role of host genetic variation in disease emergence, beyond a strict focus on the evolutionary properties of viruses. The project will aid in our understanding of the evolutionary processes leading to the emergence of new diseases. It is significant because the work here will be widely applicable to diverse viruses beyond lentiviruses, and to host barriers beyond receptor blocks.