2. Academic Validation
  3. The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression

The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression

  • Cell. 2024 Feb 29;187(5):1223-1237.e16. doi: 10.1016/j.cell.2024.01.048.
Qiankun Wang 1,  Kolin M Clark 1,  Ritudhwaj Tiwari 1,  Nagarajan Raju 2,  Gregory K Tharp 2,  Jeffrey Rogers 3,  R Alan Harris 3,  Muthuswamy Raveendran 3,  Steven E Bosinger 4,  Tricia H Burdo 5,  Guido Silvestri 4,  Liang Shan 6
Affiliations

Affiliations

  • 1 Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
  • 2 Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
  • 3 Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
  • 5 Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
  • 6 Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: liang.shan@wustl.edu.
PMID: 38428396 DOI: 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.

Keywords

CARD8; CD4(+) T cells; HIV; SIV; caspase 1; inflammasome; non-human primates; pyroptosis; viral entry; viral protease.

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