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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Adult
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Anti-HIV Agents / pharmacology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology*
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Caspase 1 / metabolism*
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Caspase 3 / metabolism
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Caspase Inhibitors / administration & dosage
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Caspase Inhibitors / pharmacology
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Cell Death / drug effects
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HIV Infections / drug therapy
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HIV Infections / enzymology
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HIV Infections / immunology*
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HIV Infections / pathology*
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HIV-1 / drug effects
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HIV-1 / growth & development
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HIV-1 / pathogenicity*
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Humans
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In Vitro Techniques
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Inflammasomes / immunology
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Inflammasomes / metabolism
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Inflammation / complications
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Inflammation / immunology
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Inflammation / pathology
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Inflammation / virology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / metabolism
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Lymph Nodes / enzymology
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Male
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Palatine Tonsil / drug effects
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Palatine Tonsil / virology
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Protein Precursors / biosynthesis
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Spleen / drug effects
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Spleen / virology
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Virus Replication
Substances
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Anti-HIV Agents
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Caspase Inhibitors
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Inflammasomes
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Interleukin-1beta
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Protein Precursors
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Caspase 3
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Caspase 1