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

Details

• Alternative Title:
  Nature
• Personal Author:
  Doitsh, Gilad ; Galloway, Nicole LK ; Geng, Xin ; Yang, Zhiyuan ; Monroe, Kathryn M. ; Zepeda, Orlando ; Hunt, Peter W. ; Hatano, Hiroyu ; Sowinski, Stefanie ; Muñoz-Arias, Isa ; Greene, Warner C.
• Description:
  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.
• Subjects:
  Administration, Oral Adult Anti-HIV Agents Caspase 1 Caspase 3 Caspase Inhibitors CD4-Positive T-Lymphocytes Cell Death HIV-1 HIV Infections Humans Inflammasomes Inflammation Interleukin-1beta In Vitro Techniques Lymph Nodes Male Palatine Tonsil Protein Precursors Spleen Virus Replication

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• Source:
  Nature. 505(7484):509-514
• Pubmed ID:
  24356306
• Pubmed Central ID:
  PMC4047036
• Document Type:
  Journal Article
• Funding:
  L60 MD003100/MD/NIMHD NIH HHSUnited States/ ; NIH P30 AI027763/AI/NIAID NIH HHSUnited States/ ; P30 AI027763/AI/NIAID NIH HHSUnited States/ ; R21 AI102782/AI/NIAID NIH HHSUnited States/ ; U19 AI096113/AI/NIAID NIH HHSUnited States/ ; R21AI102782/AI/NIAID NIH HHSUnited States/ ; 1DP1036502/DP/NCCDPHP CDC HHSUnited States/ ; T32 AI060537/AI/NIAID NIH HHSUnited States/ ; U19AI0961133/AI/NIAID NIH HHSUnited States/ ; DP1 DA036502/DA/NIDA NIH HHSUnited States/
• Volume:
  505
• Issue:
  7484
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:cd0f6b99ef194461d709fd108e3e8a76f035528b2d335a265674096f0d3d5176
• Download URL:
  https://stacks.cdc.gov/view/cdc/29985/cdc_29985_DS1.pdf
• File Type:
  [PDF - 1.57 MB ]