After treatment with antiretroviral therapy, HIV-1 wild-type and escape variants may persist in a latent form, especially within CD4+ T cells, which inhibit attempts to eradicate the virus. V. Wang et al. found that human CARD8, a member of the caspase recruitment domain (CARD) -containing family of innate immune sensors, can be activated 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 unlabeled 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 could be a promising way to eliminate residual HIV-1 in patients.
Science, this issue p. eabe1707