title: Association of IL-10-promoter genetic variants with the rate of CD4 T-cell loss, IL-10 plasma levels, and breadth of cytotoxic T-cell lymphocyte response during chronic HIV-1 infection.
abstract: BACKGROUND
  Interleukin-10 (IL-10) is a potent immunoregulatory cytokine. IL-10-promoter polymorphisms have been shown to affect human immunodeficiency virus type 1 (HIV-1) clinical outcomes but the underlying mechanisms are poorly understood.
  
  
  METHODS
  We investigated the relationship between IL-10-promoter variants, plasma cytokine levels, immune responses and markers of disease outcome in antiretroviral-naïve HIV-1 chronically infected individuals from South Africa. Two IL-10-promoter single nucleotide polymorphisms (SNPs) were genotyped in 451 participants. Baseline plasma levels of select cytokines were measured for 112 individuals. Viral load, CD4(+) T-cell counts and HIV-1-specific interferon-gamma CD8(+) T-cell immune responses were measured at baseline. CD4(+) T-cell counts were measured longitudinally and rates of CD4(+) T-cell decline computed for 300 study subjects.
  
  
  RESULTS
  The minor IL-10-1082G and -592A variants occurred at frequencies of 0.31 and 0.34, respectively. The -592AA genotype associated significantly with attenuated loss of CD4(+) T cells (P = .0496). Individuals possessing -1082GG had significantly higher IL-10 levels compared to -1082AA/AG (P = .0006). The -592AA genotype was associated with greater breadth of virus-specific CD8(+) T-cell responses compared to CC and CA (P = .002 and .004 respectively).
  
  
  CONCLUSIONS
  IL-10-promoter variants may influence the rate of HIV-1 disease progression by regulating IL-10 levels and the breadth of CD8(+) T-cell immune responses.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Dshanta D
authors.initials: DD
authors.lastname: Naicker
authors.forename: Bingxia
authors.initials: B
authors.lastname: Wang
authors.forename: Elena
authors.initials: E
authors.lastname: Losina
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zupkosky
authors.forename: Susan
authors.initials: S
authors.lastname: Bryan
authors.forename: Shabashini
authors.initials: S
authors.lastname: Reddy
authors.forename: Manjeetha
authors.initials: M
authors.lastname: Jaggernath
authors.forename: Mammekwa
authors.initials: M
authors.lastname: Mokgoro
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics* / Q000276:immunology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018709:Statistics, Nonparametric; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load
chemical_list: D016753:Interleukin-10; D007371:Interferon-gamma
references.citation: Physiol Rev. 2006 Apr;86(2):515-81
references.pmid: 16601268
references.citation: J Exp Med. 2006 Oct 30;203(11):2461-72
references.pmid: 17030951
references.citation: Lancet. 2008 Nov 29;372(9653):1894-1905
references.pmid: 19012957
references.citation: Nature. 2004 Dec 9;432(7018):769-75
references.pmid: 15592417
references.citation: Science. 2004 Feb 13;303(5660):954-5
references.pmid: 14963308
references.citation: J Pathol. 2008 Jan;214(2):224-30
references.pmid: 18161757
references.citation: J Virol. 2001 Feb;75(3):1339-47
references.pmid: 11152507
references.citation: Blood. 1998 Nov 15;92(10):3943-8
references.pmid: 9808588
references.citation: Virology. 2006 Sep 1;352(2):485-92
references.pmid: 16781761
references.citation: Blood. 2004 May 1;103(9):3529-34
references.pmid: 14701701
references.citation: Am J Epidemiol. 2004 Dec 1;160(11):1033-8
references.pmid: 15561982
references.citation: Nat Med. 1996 Apr;2(4):412-7
references.pmid: 8597950
references.citation: Turk J Haematol. 2005 Dec 5;22(4):191-6
references.pmid: 27265011
references.citation: Annu Rev Med. 2003;54:535-51
references.pmid: 12525683
references.citation: Blood. 2006 May 15;107(10):4101-8
references.pmid: 16449530
references.citation: J Med Genet. 1994 Feb;31(2):89-98
references.pmid: 8182727
references.citation: J Reprod Immunol. 2006 Dec;72(1-2):118-26
references.pmid: 16863661
references.citation: Nat Med. 2007 Jan;13(1):46-53
references.pmid: 17173051
references.citation: Blood. 2009 Jul 9;114(2):346-56
references.pmid: 19365081
references.citation: Nat Med. 2006 Nov;12(11):1301-9
references.pmid: 17041596
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9465-70
references.pmid: 9689103
references.citation: J Clin Invest. 2010 Jun;120(6):1905-13
references.pmid: 20440075
references.citation: Science. 2007 Aug 17;317(5840):944-7
references.pmid: 17641165
references.citation: J Infect Dis. 2009 Aug 1;200(3):448-52
references.pmid: 19534595
references.citation: J Infect Dis. 2006 Jan 1;193(1):16-26
references.pmid: 16323127
references.citation: AIDS. 2009 Jan 2;23(1):9-18
references.pmid: 19050381
references.citation: Lancet. 2008 Nov 29;372(9653):1881-1893
references.pmid: 19012954
references.citation: Genes Immun. 2009 Jun;10(4):309-22
references.pmid: 19295541
references.citation: Trends Immunol. 2008 Mar;29(3):116-24
references.pmid: 18258483
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14467-72
references.pmid: 11121048
references.citation: J Immunol. 2001 Mar 15;166(6):4244-53
references.pmid: 11238678
references.citation: AIDS. 2007 Nov 12;21(17):2283-91
references.pmid: 18090276
references.citation: J Biol Chem. 2010 Jun 11;285(24):18319-25
references.pmid: 20378550
references.citation: Genes Immun. 2003 Sep;4(6):441-9
references.pmid: 12944981
references.citation: J Virol. 1999 Dec;73(12):10264-71
references.pmid: 10559343
references.citation: J Immunol. 2001 Mar 15;166(6):3915-22
references.pmid: 11238636
references.citation: Retrovirology. 2010 Apr 09;7:33
references.pmid: 20380696
references.citation: J Infect Dis. 2009 Feb 1;199(3):419-26
references.pmid: 19115949