title: Complementary role of HCV and HIV in T-cell activation and exhaustion in HIV/HCV coinfection.
abstract: OBJECTIVE
  To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls.
  
  
  METHODS
  14 HIV/HCV coinfected, 19 HCV monoinfected, 10 HIV monoinfected patients and 15 healthy controls were included in this cross-sectional study. Differences in expression of activation and exhaustion markers (HLA-DR, CD38, PD-1, Tim-3 and Fas) and phenotypic markers on CD4(+) and CD8(+) T-cells were analysed by flow cytometry and were related to HCV disease parameters (HCV-viremia, ALT and liver fibrosis).
  
  
  RESULTS
  Frequencies of activated CD4(+) and CD8(+) T-cells were higher in HIV/HCV-coinfected compared to healthy controls and HCV or HIV mono-infected individuals. Coinfected patients also showed high expression of the exhaustion marker PD-1 and death receptor Fas. In contrast, the exhaustion marker Tim-3 was only elevated in HIV-monoinfected patients. T-cell activation and exhaustion were correlated with HCV-RNA, suggesting that viral antigen influences T-cell activation and exhaustion. Interestingly, increased percentages of effector CD8(+) T-cells were found in patients with severe (F3-F4) liver fibrosis compared to those with no to minimal fibrosis (F0-F2).
  
  
  CONCLUSIONS
  HIV/HCV coinfected patients display a high level of T-cell activation and exhaustion in the peripheral blood. Our data suggest that T-cell activation and exhaustion are influenced by the level of HCV viremia. Furthermore, high percentages of cytotoxic/effector CD8(+) T-cells are associated with liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients.
authors.affiliation: Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: Feuth
authors.forename: Joop E
authors.initials: JE
authors.lastname: Arends
authors.forename: Justin H
authors.initials: JH
authors.lastname: Fransen
authors.forename: Nening M
authors.initials: NM
authors.lastname: Nanlohy
authors.forename: Karel J
authors.initials: KJ
authors.lastname: van Erpecum
authors.forename: Peter D
authors.initials: PD
authors.lastname: Siersema
authors.forename: Andy I M
authors.initials: AI
authors.lastname: Hoepelman
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D016022:Case-Control Studies; D060085:Coinfection; D003430:Cross-Sectional Studies; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000473:pathology / Q000821:virology*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D006684:HLA-DR Antigens
references.citation: Curr Opin HIV AIDS. 2011 Nov;6(6):472-7
references.pmid: 21918438
references.citation: J Virol. 2009 Nov;83(21):11407-11
references.pmid: 19710147
references.citation: J Acquir Immune Defic Syndr. 2011 May 1;57(1):1-8
references.pmid: 21786458
references.citation: J Viral Hepat. 2010 Jul;17(7):453-8
references.pmid: 20487259
references.citation: J Infect Dis. 2006 May 1;193(9):1202-10
references.pmid: 16586355
references.citation: J Immunol Methods. 2000 Oct 20;244(1-2):139-44
references.pmid: 11033026
references.citation: J Immunol Methods. 2003 Jul;278(1-2):145-55
references.pmid: 12957403
references.citation: Apoptosis. 2011 Sep;16(9):959-66
references.pmid: 21667042
references.citation: Gut. 2012 Aug;61(8):1226-34
references.pmid: 21873736
references.citation: J Immunol. 2006 Jul 1;177(1):729-38
references.pmid: 16785572
references.citation: Curr HIV Res. 2003 Oct;1(4):405-17
references.pmid: 15049427
references.citation: Nat Med. 2006 Dec;12(12):1365-71
references.pmid: 17115046
references.citation: N Engl J Med. 2007 Apr 5;356(14):1445-54
references.pmid: 17409326
references.citation: Nature. 2006 Feb 9;439(7077):682-7
references.pmid: 16382236
references.citation: Atherosclerosis. 2012 May;222(1):274-7
references.pmid: 22417840
references.citation: Viral Immunol. 2009 Feb;22(1):39-48
references.pmid: 19210227
references.citation: PLoS Med. 2006 Dec;3(12):e492
references.pmid: 17194190
references.citation: Nat Immunol. 2011 Jun;12(6):492-9
references.pmid: 21739672
references.citation: Lancet Infect Dis. 2004 Jul;4(7):437-44
references.pmid: 15219554
references.citation: BMC Infect Dis. 2012 Apr 25;12:102
references.pmid: 22533731
references.citation: J Infect Dis. 2008 Jan 1;197(1):126-33
references.pmid: 18171295
references.citation: Virulence. 2010 May-Jun;1(3):177-9
references.pmid: 21178437
references.citation: Eur J Immunol. 2010 Mar;40(3):859-66
references.pmid: 20049876
references.citation: Clin Infect Dis. 2006 Nov 1;43(9):1209-12
references.pmid: 17029144
references.citation: J Virol. 2004 Jun;78(11):5535-45
references.pmid: 15140950
references.citation: J Clin Microbiol. 1993 Oct;31(10):2679-82
references.pmid: 8253965
references.citation: Hepatology. 2008 Jun;47(6):1824-36
references.pmid: 18454507
references.citation: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5692-7
references.pmid: 10318946
references.citation: Semin Liver Dis. 2010 Aug;30(3):226-31
references.pmid: 20665375
references.citation: J Exp Med. 2006 Oct 2;203(10):2223-7
references.pmid: 17000870
references.citation: Eur J Immunol. 2005 Dec;35(12):3493-504
references.pmid: 16304636
references.citation: J Exp Med. 1993 Jul 1;178(1):17-25
references.pmid: 8100267
references.citation: Clin Sci (Lond). 2007 Feb;112(3):141-55
references.pmid: 17199558
references.citation: J Immunol. 2008 Jul 15;181(2):1573-81
references.pmid: 18606713
references.citation: Eur J Immunol. 2010 Sep;40(9):2493-505
references.pmid: 20623550
references.citation: AIDS. 2002 Sep 27;16(14):1859-66
references.pmid: 12351945
references.citation: AIDS. 2000 Dec 1;14(17):2643-51
references.pmid: 11125882
references.citation: Cell. 2000 Mar 17;100(6):655-69
references.pmid: 10761931
references.citation: Antiviral Res. 2010 Sep;87(3):353-60
references.pmid: 20547185
references.citation: Top HIV Med. 2009 Sep-Oct;17(4):118-23
references.pmid: 19890183
references.citation: J Viral Hepat. 1999 May;6(3):203-8
references.pmid: 10607232
references.citation: Hepatology. 1997 Mar;25(3):705-12
references.pmid: 9049223
references.citation: Nat Immunol. 2011 May 29;12(7):663-71
references.pmid: 21623380
references.citation: Proc Natl Acad Sci U S A. 2009 May 26;106(21):8623-8
references.pmid: 19433785
references.citation: J Immunol. 1997 Jun 1;158(11):5283-91
references.pmid: 9164947
references.citation: J Infect Dis. 2009 Mar 1;199(5):726-36
references.pmid: 19199548
references.citation: J Exp Med. 1997 Nov 3;186(9):1407-18
references.pmid: 9348298
references.citation: J Med Virol. 2007 May;79(5):503-10
references.pmid: 17385690