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

2013; Nature Portfolio; Volume: 505; Issue: 7484 Linguagem: Inglês

10.1038/nature12940

1476-4687

Gilad Doitsh, Nicole Galloway, Xin Geng, Zhiyuan Yang, Kathryn M. Monroe, Orlando Zepeda, Peter W. Hunt, Hiroyu Hatano, Stefanie Sowinski, Isa Muñoz-Arias, Warner C. Greene,

Autoimmune and Inflammatory Disorders Research

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. Quiescent CD4 T cells in lymphoid tissues are shown to die after HIV-1 infection by caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death; caspase 1 inhibitors, which are safe for human use, can rescue the cell death in vitro raising the possibility of new therapeutics targeting the host instead of the virus. The loss of CD4 T cells — helper T cells carrying receptors that recognize the CD4 antigen on the surface of virus-infected cells — lies at the root of AIDS pathogenesis. In this study Warner Greene et al. identify the mechanism through which quiescent lymphoid CD4 T cells are depleted during HIV infection. Using ex vivo cultures of human lymphoid tissue that preserve the natural lymphoid environment, the authors show that abortive viral replication triggers caspase-1-mediated pyroptosis, which is responsible for the cell death. Caspase 1 inhibitors — which have been shown to be safe in clinical trials — can rescue the cell death in vitro, suggesting a possible new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.