Abstract

Inflammasomes are multi-protein signaling complexes formed in the cytosol to ignite innate immune defense by sensing pathogens and damage signals. During HIV infection, CARD8 is a bona-fide inflammasome sensor that detects HIV protease activity for the activation of caspase-1 and subsequent pyroptotic cell death of CD4+ T cells. However, in the case of active infection, CARD8 sensing is avoided in earlier stages of infection because the viral PR remains inactive prior to viral budding. Therefore, there is a pressing need to understand the innate immune sensing mechanisms of HIV-1 infection in other stages of HIV-1 life cycle before viral budding. In our preliminary studies, we identified the interaction between CARD8 and RNA using cross-linking immunoprecipitation (CLIP) experiments, which generates a key hypothesis that HIV-1 RNA is a ligand that modulates CARD8 inflammasome functions. This project proposes to study the interaction between HIV-1 RNAs and CARD8 using structural and biochemical approaches.