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Summary

Inflammasomes are cytosolic innate immune complexes that play a critical role in host defense against pathogens but can also contribute to inflammatory pathogenesis. Here, we find that the human inflammasome-forming sensor CARD8 senses HIV-1 infection via site-specific cleavage of the CARD8 N-terminus by the HIV protease (HIV-1^PR). HIV-1^PR cleavage of CARD8 induces pyroptotic cell death and the release of pro-inflammatory cytokines from infected cells, processes that we find are dependent on Toll-like receptor stimulation prior to viral infection. Our evolutionary analyses reveal that the HIV-1^PR cleavage site in CARD8 is unique to humans, and that chimpanzee CARD8 does not recognize proteases from HIV or simian immunodeficiency viruses from chimpanzees (SIVcpz). In contrast, SIVcpz does cleave human CARD8, suggesting that SIVcpz was poised to activate the human CARD8 inflammasome prior to its cross-species transmission into humans and implicating the CARD8 inflammasome as a potential driver of HIV pathogenesis.