The study by Doitsh et al. investigates the mechanism of CD4 T-cell depletion in HIV-1 infection, a process that has been poorly understood. The researchers found that caspase-3-mediated apoptosis accounts for only a small fraction of CD4 T-cell death, while the majority of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis is an inflammatory form of programmed cell death where dying cells release cytoplasmic contents and pro-inflammatory cytokines, including IL-1β. This pathway links the two signature events in HIV infection—CD4 T-cell depletion and chronic inflammation—and creates a vicious cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. The study also highlights the constitutive expression of pro-IL-1β in lymphoid CD4 T cells, particularly in the CCR5-expressing subset, which could contribute to chronic inflammation. The findings suggest that targeting caspase-1 with safe and effective inhibitors, such as VX-765, could break this pathogenic cycle and potentially provide a new class of "anti-AIDS" therapeutics.The study by Doitsh et al. investigates the mechanism of CD4 T-cell depletion in HIV-1 infection, a process that has been poorly understood. The researchers found that caspase-3-mediated apoptosis accounts for only a small fraction of CD4 T-cell death, while the majority of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis is an inflammatory form of programmed cell death where dying cells release cytoplasmic contents and pro-inflammatory cytokines, including IL-1β. This pathway links the two signature events in HIV infection—CD4 T-cell depletion and chronic inflammation—and creates a vicious cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. The study also highlights the constitutive expression of pro-IL-1β in lymphoid CD4 T cells, particularly in the CCR5-expressing subset, which could contribute to chronic inflammation. The findings suggest that targeting caspase-1 with safe and effective inhibitors, such as VX-765, could break this pathogenic cycle and potentially provide a new class of "anti-AIDS" therapeutics.