CARD8 is an inflammasome sensor for HIV-1 protease activity

• Published in: Science (American Association for the Advancement of Science) 2021-03, Vol.371 (6535)
• Main Authors: Wang, Qiankun, Gao, Hongbo, Clark, Kolin M, Mugisha, Christian Shema, Davis, Keanu, Tang, Jack P, Harlan, Gray H, DeSelm, Carl J, Presti, Rachel M, Kutluay, Sebla B, Shan, Liang
• Format: Article
• Language: English
• Subjects: Adaptive systems; Alkynes - pharmacology; Amino acids; Anti-HIV Agents - pharmacology; Antibodies; Antiretroviral agents; Apoptosis; Assembly; Benzoxazines - pharmacology; CARD Signaling Adaptor Proteins - chemistry; CARD Signaling Adaptor Proteins - metabolism; Caspase 1 - metabolism; CD4-Positive T-Lymphocytes - physiology; CD4-Positive T-Lymphocytes - virology; Cell death; Cleavage; Cyclopropanes - pharmacology; Dimerization; Drug therapy; Enzyme Activation; Eradication; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Protease - metabolism; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immune system; Infections; Inflammasomes; Inflammasomes - metabolism; Inhibitors; Leucine; Lymphocytes; Macrophages; Macrophages - physiology; Macrophages - virology; Microorganisms; Mortality; Mutation; Neoplasm Proteins - chemistry; Neoplasm Proteins - metabolism; Nucleosides; Nucleotides; Oligomerization; Patients; Pattern recognition; Persistence; Polypeptides; Protease; Proteasomes; Proteins; Pyroptosis; Recruitment; Reverse Transcriptase Inhibitors - pharmacology; Rilpivirine - pharmacology; Sensors; Sequences; THP-1 Cells; Virus Latency
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abe1707

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 targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before 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 the clearance of persistent HIV-1 infection.