Language
English
Publication Date
2-29-2024
Journal
Cell
DOI
10.1016/j.cell.2024.01.048
PMID
38428396
PMCID
PMC10919936
PubMedCentral® Posted Date
2-28-2025
PubMedCentral® Full Text Version
Author MSS
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 do 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.
Keywords
Animals, Humans, Mice, CARD Signaling Adaptor Proteins, CD4-Positive T-Lymphocytes, Disease Progression, HIV Infections, Inflammasomes, Neoplasm Proteins, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, Viremia, HIV
Published Open-Access
yes
Recommended Citation
Wang, Qiankun; Clark, Kolin M; Tiwari, Ritudhwaj; et al., "The CARD8 Inflammasome Dictates HIV/Siv Pathogenesis and Disease Progression" (2024). Faculty and Staff Publications. 5093.
https://digitalcommons.library.tmc.edu/baylor_docs/5093
Graphical Abstract
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons