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Nature. 2014 Jan 23;505(7484):509-14. doi: 10.1038/nature12940.

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

Author information

1
1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2].
2
Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
3
Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA.
4
1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2] Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA [3] Department of Microbiology and Immunology, 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.

PMID:
24356306
PMCID:
PMC4047036
DOI:
10.1038/nature12940
[Indexed for MEDLINE]
Free PMC Article

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