The CARD8 inflammasome drives CD4+ T-cell depletion in HIV-1 infection

CD4+ T-cell depletion is the root cause of acquired immunodeficiency syndrome (AIDS). How HIV depletes CD4+ T cells in humans remains unknown because vast majority of the dying CD4+ T cells in patients are uninfected. Burgeoning evidence supports the hypothesis that non-productive HIV-1 infection triggers CD4+ T-cell depletion in the course of pathogenic HIV and SIV infections. Here, we report that the CARD8 inflammasome is activated immediately after HIV-1 entry by the viral protease encapsulated in the incoming HIV-1 particles. Sensing of HIV-1 protease activity by the CARD8 inflammasome leads to rapid pyroptosis of quiescent CD4+ T cells without productive viral infection. In humanized mice reconstituted with a CARD8-deficient immune system, CD4+ T-cell loss is delayed despite increased levels of HIV-1 replication. Our study suggests that the CARD8 inflammasome drives CD4+ T-cell depletion and disease progression through rapid sensing of HIV-1 particles.