Progressive depletion of CD4 T cells is a hallmark of HIV/SIV-induced AIDS. While HIV/SIV directly infects and kills CD4 T cells, the number of productively infected cells in vivo cannot account for the massive CD4 T-cell losses that occur. To gain a better understanding of this phenomenon, primary human lymphoid aggregate cultures (HLAC) from human tonsil and spleen tissue were examined. Three surprising discoveries emerged. 1) Quiescent "bystander" CD4 T cells, which are not permissive to productive X4-HIV infection, die in huge numbers, but their death involves abortive infection and accumulations of cytosolic HIV DNA. 2) CD4 T-cell death results from host innate immune responses elicited by cytosolic viral DNA. 3) The innate immune response activates caspase-1 and -3 and releases IL-1ß (1). These CD4 T cells potentially die via pyroptosis, a robustly inflammatory type of programmed cell death. Inflammasome activation can restrict intracellular pathogens, but during HIV infection, the process spins out of control with inflammation leading to the recruitment of new cellular targets that undergo new rounds of infection and death. Based on these findings, we hypothesize that inflammasome activation in CD4 T cells is a molecular hallmark of pathogenic HIV/SIV infection, but does not occur in nonpathogenic SIV infections. Importantly, nonpathogenic SIV infections are distinguished by a relative lack of inflammation and immune activation. These studies promise to provide exciting new perspectives on the key molecular events that distinguish pathogenic and nonpathogenic lentiviral infections. Such insights could suggest new approaches to block HIV immunopathogenesis.