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.

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HIV-1 usually utilizes CCR5 as its co-receptor and rarely switches to CXCR4-tropic until the late stage of infection. CCR5 + CD4 + T cells are the major virus-producing cells in viremic individuals as well as SIV-infected non-human primates. The differentiation of CCR5 + CD4 + T cells is associated with the availability of IL15, which increases during acute HIV-1 infection. Here, we report that CCR5 is expressed by CD4 + T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL2/IL15 receptor common beta and gamma chains. IL15 but not IL7 improves the survival of CCR5 + CD4 + T cells, drives their expansion, and facilitates HIV-1 infection in vitro and in humanized mice. Our study suggests that IL15 plays confounding roles in HIV-1 infection, and future studies on the IL15-based boosting of anti-HIV-1 immunity should carefully examine the potential effects on the expansion of HIV-1 reservoirs in CCR5 + CD4 + T cells.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) induce pyroptosis of HIV-1 infected CD4+ T cells through induction of intracellular viral protease activation, which then activates the CARD8 inflammasome. Due to high concentrations of NNRTIs being required for efficient CARD8 activation and elimination of HIV-1-infected cells, it is important to elucidate ways to sensitize the CARD8 inflammasome to NNRTI-induced activation. We show that this sensitization can be done through chemical inhibition of the CARD8 negative regulator DPP9. DPP9 inhibitor Val-boroPro (VbP) can act synergistically with NNRTIs to increase their efficacy in killing HIV-1-infected cells. We also show that VbP is able to partially overcome issues with NNRTI resistance and is capable of killing infected cells without the presence of NNRTIs. This offers a promising strategy for enhancing NNRTI efficacy in elimination of HIV-1 reservoirs in patients.