Pyroptosis drives CD4 T-cell depletion in HIV-1 infection

By G. Doitsh, N. Galloway, X. Geng, Zhiyuan Yang, K. Monroe, O. Zepeda, P. Hunt, H. Hatano, S. Sowinski, Isa Muñoz-Arias and 1 more. Nature, 2013

1,127 citations recorded by the source corpus.

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.

Subfields: Hematology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f3d7570806a189cd3a34d0f67e25d763570ca7e1

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Citations in the corpus

Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production (2014, positive): “Evidence that VX-765 can block the pyroptotic death of HIV-infected CD4 T cells (Doitsh et al., 2014) has added to the hope that caspase inhibitors may yet find clinical application.”
Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, background): “During HIV abortive infection, the engagement of the interferon-gamma-inducible-protein 16 (IFI16) in response to cytosolic viral DNA leads to inflammasome assembly and caspase-1 mediated CD4T cells pyroptosis in lymphoid tissues (181, 182).”
Mechanisms and functions of inflammasomes. (2014, background): “In this regard, activation of caspase-1 and pyroptosis in quiescent CD4 T cells was recently proposed to underlie the immunosuppressive and chronic inflammatory condition of HIV-infected individuals (Doitsh et al., 2014).”
Caspases in Cell Death, Inflammation, and Gasdermin-Induced Pyroptosis (2020, background): “Caspase-1-induced pyroptotic cell death in HIV-infected lymphoid CD4+ T cells is a major cause of depletion of CD4+ T cells in HIV infection (112, 113).”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “Macrophage: CASP1 activation [23, 186] Macrophage: CASP3/7/8 activation [23] Macrophage: pMLKL [23] Human immunodeficiency virus (ssRNA) T cell: CASP1 activation and IL-1β release [189] T cell: CASP3 activation [190] N/A”
Pyroptotic cell death defends against intracellular pathogens (2015, background): “(60) recently demonstrated that CD4 T-cell death is a result of caspase-1-dependent pyroptosis.”