Publication Date:
2013-12-21
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-1beta, 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047036/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047036/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Doitsh, Gilad -- Galloway, Nicole L K -- Geng, Xin -- Yang, Zhiyuan -- Monroe, Kathryn M -- Zepeda, Orlando -- Hunt, Peter W -- Hatano, Hiroyu -- Sowinski, Stefanie -- Munoz-Arias, Isa -- Greene, Warner C -- 1DP1036502/DP/NCCDPHP CDC HHS/ -- DP1 DA036502/DA/NIDA NIH HHS/ -- NIH P30 AI027763/AI/NIAID NIH HHS/ -- P30 AI027763/AI/NIAID NIH HHS/ -- R21 AI102782/AI/NIAID NIH HHS/ -- R21AI102782/AI/NIAID NIH HHS/ -- T32 AI060537/AI/NIAID NIH HHS/ -- U19 AI096113/AI/NIAID NIH HHS/ -- U19AI0961133/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Jan 23;505(7484):509-14. doi: 10.1038/nature12940.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2]. ; Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA. ; Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, California 94143, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24356306" target="_blank"〉PubMed〈/a〉
Keywords:
Administration, Oral
;
Adult
;
Anti-HIV Agents/pharmacology
;
CD4-Positive T-Lymphocytes/cytology/drug effects/*pathology/secretion
;
Caspase 1/*metabolism
;
Caspase 3/metabolism
;
Caspase Inhibitors/administration & dosage/pharmacology
;
Cell Death/drug effects
;
HIV Infections/drug therapy/enzymology/*immunology/*pathology
;
HIV-1/drug effects/growth & development/*pathogenicity
;
Humans
;
In Vitro Techniques
;
Inflammasomes/immunology/metabolism
;
Inflammation/complications/immunology/pathology/virology
;
Interleukin-1beta/biosynthesis/secretion
;
Lymph Nodes/enzymology
;
Male
;
Palatine Tonsil/drug effects/virology
;
Protein Precursors/biosynthesis
;
Spleen/drug effects/virology
;
Virus Replication
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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