CARD8 inflammasome mediates pyroptosis of HIV-1-infected cells by sensing viral protease activity

Abstract

HIV-1 has high mutation rates and exists as mutant swarms in the host. Rapid evolution of HIV-1 allows the virus to outpace host immune system, leading to viral persistence. Novel approaches to target immutable components are needed to clear HIV-1 infection. Here we report a pattern-recognition receptor CARD8 that senses enzymatic activity of the HIV-1 protease, which is indispensable for the virus. All subtypes of HIV-1 can be sensed by CARD8 despite substantial viral diversity. HIV-1 evades CARD8 sensing because the viral protease remains inactive in infected cells prior to viral budding. Induction of premature intracellular activation of the viral protease triggers CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy leads to clearance of latent HIV-1 in patient CD4+ T cells after virus reactivation. Taken together, our study identifies CARD8 as an inflammasome sensor of HIV-1 that holds promise as a strategy for clearance of persistent HIV-1 infection.

Structural mechanism of CARD8 regulation by DPP9

“…For example, CARD8 and NLRP1 may have evolved to respond to different pathogens. Consistent with this idea, recent reports revealed that human rhinovirus 3C protease and HIV protease directly cleave and activate human NLRP1 and CARD8, respectively (Robinson et al, 2020;Tsu et al, 2020;Wang et al, 2020). Moreover, human NLRP1 was also recently reported to sense intracellular long doublestranded RNAs by directly binding them through its leucine-rich repeat (LRR) domain (Bauernfried et al, 2020), which is absent in CARD8.…”