Most CD4 T cells dying during HIV infection are resting “bystander” CD4 T that undergo abortive viral infection arresting during the reverse transcription (Doitsh et al., Cell 2010). IFI16-mediated sensing of the cytosolic viral DNA that accumulates in these cells (Monroe et al, Science 2014) induces inflammasome assembly and caspase-1 activation. The cells die by caspase-1 dependent pyroptosis, a highly inflammatory form of programmed cell death (Doitsh et al, Nature 2014) Recent studies demonstrate that cell-to-cell transmission of HIV-1 is required to trigger this response (Galloway et al, Cell Reports, 2015). Unlike lymphoid tissue CD4 T cells, peripheral blood CD4 T cells are highly resistant to this form of cell death due in part to a deeper resting state. Remarkably these blood CD4 T cells become sensitive to pyroptosis when mixed with a variety of lymphoid tissue cells (Munoz Arias et al, Cell Host Microbe, 2015). Pyroptosis also occurs in vivo in humanized mice acutely infected with R5-tropic HIV. Three days post-infection, the TKO-BLT animals were treated with VX-765, a selective caspase-1 inhibitor that has been shown to be safe and well tolerated in 2-phase II human trials. VX-765 markedly blocked CD4 T cell depletion while not altering viral load and inhibited production of IL-18 (a caspase-1 substrate). Together, these studies highlight an important role for caspase-1 dependent pyroptosis as a major driver of HIV-associated CD4 T-cell depletion both in vitro and in vivo.