A new mechanism to explain massive depletion of CD4+ T cells in HIV-1 infection despite the low frequency of productively infected cells involves innate immune sensing of HIV 1 by abortively infected “bystander” CD4+ T cells. The result is death of the bystander cells through an inflammatory process known as pyroptosis. These findings may provide long sought explanations for both CD4+ T cell depletion and HIV-associated inflammation. See Article on page X.