title: Incomplete normalization of regulatory t-cell frequency in the gut mucosa of Colombian HIV-infected patients receiving long-term antiretroviral treatment.
abstract: BACKGROUND
  To evaluate the effect of late initiation of HAART and poor immune reconstitution on the frequency of regulatory T-cells (Treg) in the peripheral blood and gut of HIV-infected patients, we studied Colombian HIV-infected patients who had been on suppressive HAART for at least one year. They had undetectable viremia but were either immunological responders (HIR); (CD4 counts >500 cells/µl) or non-immunological responders (NIR); (CD4 T-cell count <300 cells/µl). Untreated HIV-infected patients and uninfected controls from the same region were also evaluated.
  
  
  METHODS
  Frequency and phenotype of regulatory T-cells (Treg) were analyzed in gut biopsies and blood samples. The functional effect of Treg depletion on CMV and HIV responses was determined. Markers of immune activation and circulating LPS levels were quantified.
  
  
  RESULTS
  Untreated patients exhibited high Treg frequency in PBMC and gut, and their Treg express high levels of CTLA-4 and PD-1. Although HAART significantly decreased mucosal Treg frequency, it did not normalize it in any of the treated groups (HIR and NIR patients). Treg normalization was observed in the blood of HIR patients following HAART, but did not occur in NIR patients. Treg from HIV-infected patients (treated or not) suppressed HIV and hCMV-specific T-cells from gut and blood. Plasma LPS levels and percentage of HLA-DR+CD38+ T-cells were significantly elevated in all infected groups compared to controls.
  
  
  CONCLUSIONS
  These findings suggest that control of viral replication is not sufficient to normalize gut Treg frequency in patients, independent of their response to HAART. Furthermore, persistence of functional Treg in the gut appears to be associated with the failure of HAART to repair mucosal damage.
authors: Grupo Inmunovirologia, Universidad de Antioquia, Medellín, Antioquia, Colombia.
authors: Cesar M
authors: CM
authors: Rueda
authors: Paula A
authors: PA
authors: Velilla
authors: Claire A
authors: CA
authors: Chougnet
authors: Maria T
authors: MT
authors: Rugeles
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D060908:CTLA-4 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D060908:CTLA-4 Antigen; D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor
references: Nat Med. 2006 Dec;12(12):1365-71
references: 17115046
references: Blood. 2004 Nov 15;104(10):3249-56
references: 15271794
references: AIDS. 2008 Nov 12;22(17):2291-302
references: 18981768
references: J Immunol. 2010 May 15;184(10):5562-70
references: 20382886
references: Int Immunol. 2009 Oct;21(10):1105-11
references: 19737784
references: Ann Intern Med. 2000 Sep 19;133(6):401-10
references: 10975957
references: Science. 1997 Jul 4;277(5322):112-6
references: 9204894
references: J Virol. 2003 Nov;77(21):11708-17
references: 14557656
references: J Virol. 2011 Nov;85(21):11422-34
references: 21880771
references: Semin Immunol. 2008 Jun;20(3):181-6
references: 18595731
references: Curr HIV/AIDS Rep. 2009 Feb;6(1):29-35
references: 19149994
references: Open Virol J. 2012;6:49-58
references: 22582105
references: J Infect Dis. 2012 May 15;205(10):1501-9
references: 22457273
references: AIDS. 2008 Oct 1;22(15):2035-8
references: 18784466
references: Viral Immunol. 2010 Feb;23(1):49-61
references: 20121402
references: Cytometry A. 2010 Jun;77(6):571-9
references: 20162533
references: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10113-8
references: 18635688
references: PLoS One. 2012;7(1):e30307
references: 22276176
references: J Immunol. 2005 Mar 15;174(6):3143-7
references: 15749840
references: J Exp Med. 2006 Jul 10;203(7):1693-700
references: 16818676
references: J Infect Dis. 2008 Aug 15;198(4):456-64
references: 18598193
references: Sci Transl Med. 2010 May 19;2(32):32ra36
references: 20484731
references: PLoS One. 2012;7(2):e31161
references: 22348047
references: AIDS. 2010 Apr 24;24(7):947-57
references: 20179574
references: PLoS One. 2011;6(12):e28118
references: 22162758
references: PLoS One. 2006 Dec 20;1:e102
references: 17183635
references: AIDS Rev. 2006 Apr-Jun;8(2):88-97
references: 16848276
references: J Infect Dis. 2009 Apr 15;199(8):1177-85
references: 19265479
references: Mucosal Immunol. 2008 Nov;1(6):475-88
references: 19079215
references: PLoS One. 2011;6(5):e20272
references: 21637802
references: AIDS Res Hum Retroviruses. 2007 Mar;23(3):438-50
references: 17411377
references: Blood. 2006 Nov 1;108(9):3072-8
references: 16728694
references: Blood. 2011 May 19;117(20):5372-80
references: 21436067
references: Blood. 2006 Dec 1;108(12):3808-17
references: 16902147
references: J Infect Dis. 2007 Feb 15;195(4):551-61
references: 17230415
references: Science. 2008 Oct 10;322(5899):271-5
references: 18845758
references: Immunol Lett. 1999 Mar;66(1-3):207-11
references: 10203056
references: Nat Med. 2011 Jul 17;17(8):989-95
references: 21765403
references: J Virol. 2004 Mar;78(5):2454-9
references: 14963140
references: Clin Infect Dis. 2009 Mar 15;48(6):787-94
references: 19193107
references: JAMA. 2012 Jul 25;308(4):387-402
references: 22820792
references: PLoS One. 2008;3(10):e3577
references: 18974782
references: Curr HIV Res. 2011 Apr;9(3):148-53
references: 21457131