Natural hosts of simian immunodeficiency virus (SIV) are African primates that have coevolved with species-species SIVs and do not progress to AIDS despite high viral loads. This is in stark contrast to the immunodeficiency observed in infection of “non-natural” hosts of SIV/HIV, Asian macaques and humans. Certain critical CD4+ T cell subsets and anatomic niches that are required for maintaining immune system homeostasis and function are infected less frequently in natural hosts than in non-natural hosts, suggesting that the determinants of virus target cells contribute to the outcome of infection. SIV and HIV target cells are largely defined by the expression of the receptor CD4 and a coreceptor. Our lab recently discovered that the entry coreceptor CCR5 is dispensable for SIV infection of the natural host sooty mangabey (SM), and then identified CXCR6 as an additional coreceptor for this SIV. In this thesis, I defined entry coreceptors of a second natural host virus, SIVagmSab that infects sabaeus African green monkeys and found that CXCR6 was a robust coreceptor for this virus as well. I also investigated coreceptor use by the HIV-1 forerunners: the natural host virus SIVmus that infects mustached monkeys and crossed into chimpanzees; and SIVcpz that infects chimpanzees and causes AIDS-like disease and crossed into humans to found HIV-1. SIVmus infected cells expressing CXCR6 and CCR5, while SIVcpz was restricted to use of CCR5, indicating that loss of CXCR6 use coincided with the emergence of pathogenesis in this lineage. Lastly, I defined expression of CXCR6 on SM lymphocytes, and found little or no CXCR6 expression on CD4+ T cell subsets that are critical in lymphocyte homeostasis, but enrichment on replenishable effector memory CD4+ T cells. CXCR6+ CD4+ T cells were largely distinct from CCR5+ CD4+ T cells, thus forming a previously unappreciated SIV target cell population in SM. These data support a model where use of CXCR6 is a common feature among natural host SIVs that targets the virus towards more expendable cell subsets, and away from critical subsets and anatomic niches that are required to maintain immune system function, thus permitting high viral replication without immunodeficiency.