The CD8+ T cel response to intracellular pathogens such as bacteria, viruses, and protozoan parasites is a key element of host resistance to infections. To generate a robust and effective immune response, CD8+ T cells must integrate pathogen-derived and micro-environmental signals, including availability of nutrients and oxygen. Together these signals regulate the changes necessary for the dramatic expansion of effector T cells armed to eliminate pathogens and for the generation of immunological memory. In these studies, we will work to understand how the highly conserved HIF pathway, which plays a central role in regulating metabolism and the response to cellular stress caused by oxygen deficiency/hypoxia, functions in CD8+ T cells. We find that the response to acute and chronic infections are differentially impacted by HIF activity, suggesting that this pathway, which has not been studied in the context of CD8+ T cell responses, controls multiple aspects of the attenuation of effector and memory T cell function, differentiation, and immunopathology. Results from these studies will provide novel insights into the CD8+ T cell immunity, a topic of significance in the development of treatment strategies and vaccines for chronic infections, emerging infectious agents, and microorganisms relevant to biodefense. Furthermore, we will study the clinical relevance of pharmacologic stabilization of HIF, a molecule targeted in numerous disease contexts, to CD8+ T cell function.