HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to target immutable components are needed to clear HIV-1 infection. Here, we report that the CARD8 inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells prior to viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for clearance of persistent HIV-1 infection.
In this issue of JEM, Nadkarni et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20212117) identify CARD8 as an innate sensor triggered by coxsackievirus B3 proteases to drive pyroptosis of aortic endothelial cells and cardiac myocytes, fueling viral replication and heart inflammation.
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