Article | Published:

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

Nature volume 505, pages 509514 (23 January 2014) | Download Citation

  • A Corrigendum to this article was published on 22 March 2017

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.

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Acknowledgements

We thank D. N. Levy for the NLENG1 plasmid; L. A. J. O’Neill for CRID3 and parthenolide; R. Collman for the HIV-1 89.6 clone; and Vertex Pharmaceuticals for the VX-765 and VRT-043198 compounds. HIV-infected lymph node tissue was obtained from the SCOPE cohort at HIV/AIDS clinic of the San Francisco General Hospital (SFGH) Positive Health Program, with the help of R. Hoh, and M. Kerbelski. We thank W. Schecter for surgical removal of the lymph nodes from HIV-infected subjects. We thank L. Napolitano and Y. Lie from Monogram Biosciences for performing Trofile assays to determine HIV co-receptor tropism in samples of HIV-infected volunteers. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: AMD3100, efavirenz and raltegravir. We thank C. Miller, director of the Gladstone Histology Core for performing the immunostaining assays and M. Cavrois, M. Gesner, and J. Tawney for assistance with flow cytometry. We also thank G. Howard and A. L. Lucido for editorial assistance; J. C. W. Carroll, G. Maki, and T. Roberts for graphics arts; and R. Givens and S. Cammack for administrative assistance. Special thanks to N. Roan for comments on the manuscript and to J. Neidleman for stimulating discussions and technical advice. We thank the NIH/NIAID for funding (R21AI102782, 1DP1036502, U19 AI0961133). Funding was also provided by the UCSF/Robert John Sabo Trust Award (G.D.) and A.P. Giannini Foundation Postdoctoral Research Fellowship (K.M.M.). We also acknowledge support from NIH P30 AI027763 (UCSF-GIVI Center for AIDS Research) for support to S.S. and Z.Y., and for Immunology Core services.

Author information

Author notes

    • Gilad Doitsh
    • , Nicole L. K. Galloway
    •  & Xin Geng

    These authors contributed equally to this work.

Affiliations

  1. Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA

    • Gilad Doitsh
    • , Nicole L. K. Galloway
    • , Xin Geng
    • , Zhiyuan Yang
    • , Kathryn M. Monroe
    • , Orlando Zepeda
    • , Stefanie Sowinski
    • , Isa Muñoz-Arias
    •  & Warner C. Greene
  2. Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA

    • Peter W. Hunt
    • , Hiroyu Hatano
    •  & Warner C. Greene
  3. Department of Microbiology and Immunology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA

    • Warner C. Greene

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Contributions

G.D. identified the involvement of caspase 1 and pyroptosis in lymphoid CD4 T-cell death by HIV-1, developed and designed most of the studies, collected the data and wrote the manuscript; N.L.K.G. performed IL-1β protein assays and examined VX-765 in HIV-infected tonsils; X.G. performed FLICA and shRNA analyses in HLACs; Z.Y. analysed caspase cleavage in HIV-infected cultures; K.M.M. examined caspase inhibitors and LDH release assays; O.Z. tested caspase inhibitors, type-I IFN, and pro-IL-1β expression; P.W.H. and H.H. provided HIV-infected lymphoid node from surgeries of SCOPE cohort patients at HIV/AIDS clinic of the San Francisco General Hospital (SFGH); I.M.-A. provided reagents and tissues; S.S. coordinated lymph node biopsies; W.C.G. supervised all of these studies and participated in the preparation of the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Warner C. Greene.

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https://doi.org/10.1038/nature12940

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