Cell-to-cell transmission of HIV-1 is required to trigger pyroptotic death of CD4 T cells in lymphoid tissue

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key player. Our studies now show that caspase-3-mediated apoptosis only mediates the death of only a small fraction (<5%) of the total CD4 T cells that correspond to activated cells. The remaining >95% of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered as a result of abortive viral infection occurring in nonpermissive resting CD4 T cells. Pyroptosis is an intensely inflammatory form of programmed cell death where cytoplasmic contents and pro-inflammatory cytokines including IL-1β and IL-18 are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--in a single process and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. This cycle can be broken with caspase-1 inhibitors, including a compound already shown to be safe and well-tolerated in humans. These inhibitors could form a new class of "anti-AIDS" therapeutics that target the host rather than the virus. We further show that cell-to-cell transmission of HIV is obligately required for the induction of pyroptosis. Cell-free HIV-1 virions, even when added in large quantities, due not suffice. These findings underscore the infected CD4 T cell as the major killing unit promoting progression to AIDS and highlight a previously unappreciated biological role for the virological synapse