title: Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.
abstract: BACKGROUND
  While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.
  
  
  METHODS
  We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.
  
  
  RESULTS
  Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P ≤ .001). A higher percentage of CD38(+)HLA-DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD28(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality.
  
  
  CONCLUSIONS
  Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
authors.affiliation: Department of Medicine, University of California San Francisco.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.affiliation: Department of Medicine, University of California San Francisco.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Carey
authors.initials: C
authors.lastname: Shive
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Brian
authors.initials: B
authors.lastname: Clagett
authors.affiliation: School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, Ohio State University, Columbus.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Funderburg
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Janet
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Department of Bioengineering and Therapeutic Sciences.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of California San Francisco.
authors.forename: Lorrie
authors.initials: L
authors.lastname: Epling
authors.affiliation: Department of Medicine, University of California San Francisco Department of Epidemiology and Biostatistics, University of California San Francisco.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.affiliation: Department of Medicine, University of California San Francisco.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Meinert
authors.affiliation: Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Van Natta
authors.affiliation: Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland Departments of Ophthalmology and Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Jabs
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
mesh_terms: D000328:Adult; D001777:Blood Coagulation; D016022:Case-Control Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000503:physiopathology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000502:physiology
keywords: CD28; CD38; CD57; D-dimer; HIV; HLA-DR; IL-6; T-cell activation; antiretroviral therapy; cytomegalovirus; gut epithelial cell barrier; hsCRP; immune activation; intestinal fatty acid binding protein (I-FABP); mortality; sCD14; zonulin-1
references.citation: Clin Infect Dis. 2012 Apr;54(7):984-94
references.pmid: 22337823
references.citation: HIV Med. 2011 Aug;12(7):394-402
references.pmid: 21251182
references.citation: J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):317-25
references.pmid: 22918156
references.citation: HIV Clin Trials. 2013 Mar-Apr;14(2):61-7
references.pmid: 23611826
references.citation: J Infect Dis. 2014 Aug 1;210(3):383-91
references.pmid: 24585899
references.citation: AIDS. 2013 Jun 1;27(9):1387-95
references.pmid: 23435298
references.citation: J Infect Dis. 2003 May 15;187(10):1534-43
references.pmid: 12721933
references.citation: Lancet. 2008 Jul 26;372(9635):293-9
references.pmid: 18657708
references.citation: AIDS. 2010 Jun 19;24(10):1527-35
references.pmid: 20467289
references.citation: J Infect Dis. 2013 Jul;208(1):50-6
references.pmid: 23089590
references.citation: Nat Med. 2006 Dec;12(12):1365-71
references.pmid: 17115046
references.citation: Diabetes Care. 2010 Oct;33(10):2244-9
references.pmid: 20664016
references.citation: PLoS Med. 2008 Oct 21;5(10):e203
references.pmid: 18942885
references.citation: Exp Gerontol. 2002 Jan-Mar;37(2-3):445-53
references.pmid: 11772532
references.citation: J Acquir Immune Defic Syndr. 2009 Jul 1;51(3):268-73
references.pmid: 19387353
references.citation: J Infect Dis. 2011 Mar 15;203(6):780-90
references.pmid: 21252259
references.citation: J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):426-34
references.pmid: 16810109
references.citation: J Infect Dis. 2010 Jun 15;201(12):1796-805
references.pmid: 20446847
references.citation: J Infect Dis. 2014 Aug 1;210(3):374-82
references.pmid: 24585893
references.citation: Bioanalysis. 2013 Jun;5(11):1397-407
references.pmid: 23742309
references.citation: J Infect Dis. 2013 Oct 15;208(8):1202-11
references.pmid: 23852127
references.citation: Sci Transl Med. 2010 May 19;2(32):32ra36
references.pmid: 20484731
references.citation: Sci Transl Med. 2013 Jul 10;5(193):193ra91
references.pmid: 23843452
references.citation: J Immunol. 2010 Mar 15;184(6):3242-9
references.pmid: 20173031
references.citation: J Infect Dis. 1999 Apr;179(4):859-70
references.pmid: 10068581
references.citation: J Acquir Immune Defic Syndr. 2011 Aug 15;57(5):371-9
references.pmid: 21646912
references.citation: J Infect Dis. 2006 Jul 1;194(1):29-37
references.pmid: 16741879
references.citation: PLoS One. 2012;7(3):e24243
references.pmid: 22448211
references.citation: J Acquir Immune Defic Syndr. 2002 Apr 1;29(4):346-55
references.pmid: 11917238
references.citation: PLoS One. 2010 Aug 03;5(8):e11937
references.pmid: 20689824
references.citation: J Acquir Immune Defic Syndr. 2010 Nov;55(3):316-22
references.pmid: 20581689
references.citation: J Infect Dis. 2011 May 15;203(10):1474-83
references.pmid: 21502083
references.citation: Physiol Rev. 2011 Jan;91(1):151-75
references.pmid: 21248165
references.citation: Int J Epidemiol. 2012 Apr;41(2):433-45
references.pmid: 22493325
references.citation: Blood. 2007 Apr 15;109(8):3351-9
references.pmid: 17158233
references.citation: J Immunol. 2006 Feb 15;176(4):2645-53
references.pmid: 16456027
references.citation: J Infect Dis. 2011 Jul 1;204(1):154-63
references.pmid: 21628670
references.citation: Blood. 2013 Jun 6;121(23):4635-46
references.pmid: 23589670
references.citation: AIDS. 2011 Nov 13;25(17):2123-31
references.pmid: 21881481
references.citation: Ann Intern Med. 2007 Jan 16;146(2):87-95
references.pmid: 17227932
references.citation: J Virol. 2005 Mar;79(6):3675-83
references.pmid: 15731261
references.citation: Lancet. 2004 Jun 26;363(9427):2116-21
references.pmid: 15220032
references.citation: AIDS. 2013 Aug 24;27(13):2101-10
references.pmid: 24326304
references.citation: AIDS. 2010 Jun 19;24(10):1509-17
references.pmid: 20505494
references.citation: Atherosclerosis. 2009 Dec;207(2):524-9
references.pmid: 19515371
references.citation: J Infect Dis. 2011 Jun 1;203(11):1637-46
references.pmid: 21592994