Title | The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Wang, Q, Clark, KM, Tiwari, R, Raju, N, Tharp, GK, Rogers, J, Harris, RA, Raveendran, M, Bosinger, SE, Burdo, TH, Silvestri, G, Shan, L |
Journal | Cell |
Volume | 187 |
Issue | 5 |
Pagination | 1223-1237.e16 |
Date Published | 2024 Feb 29 |
ISSN | 1097-4172 |
Keywords | Animals, CARD Signaling Adaptor Proteins, CD4-Positive T-Lymphocytes, Disease Progression, HIV, HIV Infections, Humans, Inflammasomes, Mice, Neoplasm Proteins, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Viremia |
Abstract | While CD4 T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4 depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4 depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4 T cell depletion during pathogenic HIV/SIV infections. |
DOI | 10.1016/j.cell.2024.01.048 |
Alternate Journal | Cell |
PubMed ID | 38428396 |
PubMed Central ID | PMC10919936 |
Grant List | R01 AI176594 / AI / NIAID NIH HHS / United States R01 AI162203 / AI / NIAID NIH HHS / United States F31 AI165251 / AI / NIAID NIH HHS / United States UM1 AI164568 / AI / NIAID NIH HHS / United States R01 AI155162 / AI / NIAID NIH HHS / United States |
The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression.
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