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Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

Author

Listed:
  • Gilad Doitsh

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Nicole L. K. Galloway

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Xin Geng

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Zhiyuan Yang

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Kathryn M. Monroe

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Orlando Zepeda

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Peter W. Hunt

    (University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA)

  • Hiroyu Hatano

    (University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA)

  • Stefanie Sowinski

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Isa Muñoz-Arias

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street)

  • Warner C. Greene

    (Gladstone Institute of Virology and Immunology, 1650 Owens Street
    University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA
    University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA)

Abstract

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection—CD4 T-cell depletion and chronic inflammation—and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of ‘anti-AIDS’ therapeutics targeting the host rather than the virus.

Suggested Citation

  • Gilad Doitsh & Nicole L. K. Galloway & Xin Geng & Zhiyuan Yang & Kathryn M. Monroe & Orlando Zepeda & Peter W. Hunt & Hiroyu Hatano & Stefanie Sowinski & Isa Muñoz-Arias & Warner C. Greene, 2014. "Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection," Nature, Nature, vol. 505(7484), pages 509-514, January.
  • Handle: RePEc:nat:nature:v:505:y:2014:i:7484:d:10.1038_nature12940
    DOI: 10.1038/nature12940
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    Cited by:

    1. Luo, Yantao & Zhang, Long & Zheng, Tingting & Teng, Zhidong, 2019. "Analysis of a diffusive virus infection model with humoral immunity, cell-to-cell transmission and nonlinear incidence," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 535(C).
    2. Shuang Gao & Hong Zhang & He Li & Tianbo Li & Aobo Du & Xiaoxu Ling & Boqun Cheng & Zhimin Zhang, 2019. "IFI16 is Required for an Oligodeoxynucleotide with CCT Repeats to Induce Type I Interferon Production in U937 Cells," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 19(4), pages 14567-14574, July.
    3. Attaullah, & Jan, Rashid & Yüzbaşı, Şuayip, 2021. "Dynamical behaviour of HIV Infection with the influence of variable source term through Galerkin method," Chaos, Solitons & Fractals, Elsevier, vol. 152(C).
    4. Zhang, Tongqian & Xu, Xinna & Wang, Xinzeng, 2023. "Dynamic analysis of a cytokine-enhanced viral infection model with time delays and CTL immune response," Chaos, Solitons & Fractals, Elsevier, vol. 170(C).
    5. Renée R. C. E. Schreurs & Athanasios Koulis & Thijs Booiman & Brigitte Boeser-Nunnink & Alexandra P. M. Cloherty & Anusca G. Rader & Kharishma S. Patel & Neeltje A. Kootstra & Carla M. S. Ribeiro, 2024. "Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Abraham J. Arenas & Gilberto González-Parra & Jhon J. Naranjo & Myladis Cogollo & Nicolás De La Espriella, 2021. "Mathematical Analysis and Numerical Solution of a Model of HIV with a Discrete Time Delay," Mathematics, MDPI, vol. 9(3), pages 1-21, January.
    7. Quentin Le Hingrat & Paola Sette & Cuiling Xu & Andrew R. Rahmberg & Lilas Tarnus & Haritha Annapureddy & Adam Kleinman & Egidio Brocca-Cofano & Ranjit Sivanandham & Sindhuja Sivanandham & Tianyu He &, 2023. "Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Farina Karim & Catherine Riou & Mallory Bernstein & Zesuliwe Jule & Gila Lustig & Strauss Graan & Roanne S. Keeton & Janine-Lee Upton & Yashica Ganga & Khadija Khan & Kajal Reedoy & Matilda Mazibuko &, 2024. "Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Christian L Althaus & Beda Joos & Alan S Perelson & Huldrych F Günthard, 2014. "Quantifying the Turnover of Transcriptional Subclasses of HIV-1-Infected Cells," PLOS Computational Biology, Public Library of Science, vol. 10(10), pages 1-11, October.

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