Untreated HIV-1 infection is characterized by a progressive depletion of CD4 T cells that clinically culminates in AIDS. Our understanding of the mechanisms underlying CD4 T-cell death remains rudimentary. By infecting lymphoid cell cultures ex vivo, we have found that the vast majority of HIV-1-infected CD4 T cells do not die as a result of productive viral infection, but rather these cells die due to abortive infection where cytosolic viral DNA triggers a suicidal antiviral innate immune response. Importantly, this cellular suicide involves the activation of caspase-1, the release of proinflammatory cytokines like IL-1? and the induction of pyroptosis, an intensely inflammatory form of programmed cell death. These findings provide a new and intriguing link between HIV-1 infection and chronic inflammation. I now propose a translational research project extending our in vitro studies of CD4 T-cell death to the analysis of blood and lymphoid tissue from HIV-1-infected subjects investigating whether caspase-1 activation, IL-1? secretion and pyroptosis are occurring in vivo. This one-year study will be partly conducted at the Infectious Diseases Institute (IDI) in Kampala, Uganda. After spending one year working at the IDI in 2011, I have been invited to return to the IDI as Director of its Translational Research Laboratory, giving me the unique opportunity as a junior faculty to build laboratory-based translational research capacity by conducting this study with the help of Ugandan students at the IDI. To analyze my data for statistical significance I will work closely with my mentor Dr. Peter Hunt and Dr. Peter Bachetti, experienced biostatisticians. Importantly, we believe that this study could set the stage for the evaluation of caspase-1 inhibitors as a novel host-directed therapy for HIV-1-infected subjects that could block clinical progression of disease.