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The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression
Wang, Qiankun Clark, Kolin M. Tiwari, Ritudhwaj Raju, Nagarajan Tharp, Gregory K. Rogers, Jeffrey Harris, R. Alan Raveendran, Muthuswamy Bosinger, Steven E. Burdo, Tricia H.
Wang, Qiankun
Clark, Kolin M.
Tiwari, Ritudhwaj
Raju, Nagarajan
Tharp, Gregory K.
Rogers, Jeffrey
Harris, R. Alan
Raveendran, Muthuswamy
Bosinger, Steven E.
Burdo, Tricia H.
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Journal article
Date
2024-02-29
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Microbiology, Immunology, and Inflammation
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https://doi.org/10.1016/j.cell.2024.01.048
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.
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Qiankun Wang, Kolin M. Clark, Ritudhwaj Tiwari, Nagarajan Raju, Gregory K. Tharp, Jeffrey Rogers, R. Alan Harris, Muthuswamy Raveendran, Steven E. Bosinger, Tricia H. Burdo, Guido Silvestri, Liang Shan, The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression, Cell, Volume 187, Issue 5, 2024, Pages 1223-1237.e16, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2024.01.048. (https://www.sciencedirect.com/science/article/pii/S009286742400117X)
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Elsevier
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Cell, Vol. 187, Iss. 5
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