title: Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.
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.
authors.affiliation: 1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2].
authors.forename: Gilad
authors.initials: G
authors.lastname: Doitsh
authors.affiliation: 1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2].
authors.forename: Nicole L K
authors.initials: NL
authors.lastname: Galloway
authors.affiliation: 1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2].
authors.forename: Xin
authors.initials: X
authors.lastname: Geng
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Monroe
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
authors.forename: Orlando
authors.initials: O
authors.lastname: Zepeda
authors.affiliation: Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.affiliation: Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA.
authors.forename: Hiroyu
authors.initials: H
authors.lastname: Hatano
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sowinski
authors.affiliation: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
authors.forename: Isa
authors.initials: I
authors.lastname: Muñoz-Arias
authors.affiliation: 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.
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D066298:In Vitro Techniques; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000821:virology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D008198:Lymph Nodes / Q000201:enzymology; D008297:Male; D014066:Palatine Tonsil / Q000187:drug effects / Q000821:virology; D011498:Protein Precursors / Q000096:biosynthesis; D013154:Spleen / Q000187:drug effects / Q000821:virology; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D061945:Caspase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D011498:Protein Precursors; D053148:Caspase 3; D020170:Caspase 1