CARD8 is an inflammasome sensor for HIV-1 protease activity

Eradicating the last vestiges of HIV After treatment with antiretroviral therapy, HIV-1 wild-type and escape variants can persist in a latent form, especially within CD4 + T cells, hindering efforts to eradicate the virus. Q. Wang et al. found that human CARD8, a member of the caspase recruitment domain (CARD)–containing family of innate immune sensors, is activatable by direct proteolysis of its N-terminus by HIV-1 protease. This cleavage should result in the programmed cell death of infected cells, but HIV-1 protease remains inactive and undetected as a subunit of the unprocessed Gag-Pol polyprotein. However, when infected cells were treated with non-nucleoside reverse transcriptase inhibitors, intracellular Gag-Pol dimerization was enhanced, resulting in CARD8-mediated caspase activation and pyroptosis. Targeting this pathway may be a promising way to eliminate residual HIV-1 in patients. Science , this issue p. eabe1707