After treatment with antiretroviral therapy, wild-type and escape variants of HIV-1 may persist in a latent form, especially in CD4 T cells, hindering attempts 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 is not detected as a subunit of the raw Gag-Pol polyprotein. However, when infected cells were treated with non-nucleoside reverse transcriptase inhibitors, the intracellular Gag-Pol dimerization was enhanced resulting in CARD8-mediated caspase activation and pyroptose. Approaching this pathway may be a promising way to eliminate residual HIV-1 in patients.
Science, this issue p. eabe1707