title: CCR5 blockade is well tolerated and induces changes in the tissue distribution of CCR5+ and CD25+ T cells in healthy, SIV-uninfected rhesus macaques.
abstract: BACKGROUND
  CCR5 is a main co-receptor for HIV, but also homes lymphocytes to sites of inflammation. We hypothesized that inhibition of CCR5 signaling would reduce HIV-associated chronic immune activation.
  
  
  METHODS
  To test this hypothesis, we administered an antagonistic anti-CCR5 monoclonal antibody (HGS101) to five uninfected rhesus macaques (RMs) and monitored lymphocyte dynamics in blood and tissue.
  
  
  RESULTS
  CCR5 blockade resulted in decreased levels of CCR5+ T cells in blood and, at later timepoints, in lymph nodes. Additionally, the levels of CD25+ T cells increased in lymph nodes, but decreased in blood, bone marrow, and rectal mucosa. Finally, a profile of gene expression from HGS101-treated RMs revealed a subtle, but consistent, in vivo signature of CCR5 blockade that suggests a mild immune-modulatory effect.
  
  
  CONCLUSIONS
  Treatment with anti-CCR5 antibody induces changes in the tissue distribution of CCR5+ and CD25+ T cells that may impact on the overall levels of immune activation during HIV and SIV infection.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Taaffe
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.forename: Gregory Q
authors.initials: GQ
authors.lastname: Del Prete
authors.forename: James G
authors.initials: JG
authors.lastname: Else
authors.forename: Sarah
authors.initials: S
authors.lastname: Ratcliffe
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ward
authors.forename: Thi
authors.initials: T
authors.lastname: Migone
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D005434:Flow Cytometry / Q000662:veterinary; D016130:Immunophenotyping / Q000662:veterinary; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008137:Longitudinal Studies; D008221:Lymphoid Tissue / Q000276:immunology*; D008253:Macaca mulatta / Q000097:blood / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D019713:Receptors, CCR5 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D015302:Simian Immunodeficiency Virus; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D053645:Interleukin-2 Receptor alpha Subunit; D019713:Receptors, CCR5; D012313:RNA
references.citation: JAMA. 2006 Aug 16;296(7):815-26
references.pmid: 16905787
references.citation: Immunity. 2003 Mar;18(3):441-52
references.pmid: 12648460
references.citation: Immunity. 2006 May;24(5):575-90
references.pmid: 16713975
references.citation: J Immunol. 2010 Jul 1;185(1):597-604
references.pmid: 20525885
references.citation: J Exp Med. 1988 Mar 1;167(3):840-52
references.pmid: 3127527
references.citation: Mol Cell Biol. 2004 Feb;24(3):1341-50
references.pmid: 14729977
references.citation: Nature. 1996 Nov 14;384(6605):184-7
references.pmid: 8906796
references.citation: Cell Stress Chaperones. 2002 Jul;7(3):309-16
references.pmid: 12482206
references.citation: Blood. 2009 Jun 4;113(23):5801-10
references.pmid: 19346499
references.citation: Mol Cell. 2001 Oct;8(4):781-94
references.pmid: 11684014
references.citation: J Infect Dis. 2007 Jul 15;196(2):304-12
references.pmid: 17570119
references.citation: J Virol. 2010 Jun;84(11):5476-84
references.pmid: 20335252
references.citation: Immunity. 2009 Jul 17;31(1):122-30
references.pmid: 19592277
references.citation: Am J Pathol. 2001 Nov;159(5):1701-10
references.pmid: 11696431
references.citation: J Immunol. 2002 Sep 15;169(6):2851-60
references.pmid: 12218097
references.citation: J Immunol. 2007 Feb 1;178(3):1680-91
references.pmid: 17237418
references.citation: J Biol Chem. 2010 Jul 16;285(29):22328-37
references.pmid: 20463015
references.citation: Nat Cell Biol. 2004 May;6(5):436-42
references.pmid: 15122268
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6939-42
references.pmid: 9192670
references.citation: J Virol. 1998 May;72(5):3872-86
references.pmid: 9557672
references.citation: Immunology. 2002 Jan;105(1):9-19
references.pmid: 11849310
references.citation: Immunity. 1998 Jul;9(1):93-103
references.pmid: 9697839
references.citation: J Infect Dis. 2010 Mar 15;201(6):803-13
references.pmid: 20151839
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6653-8
references.pmid: 16617118
references.citation: J Immunol. 2007 Jun 15;178(12):7632-9
references.pmid: 17548599
references.citation: J Exp Med. 1988 Jul 1;168(1):127-42
references.pmid: 3260935
references.citation: J Immunol. 2002 Sep 15;169(6):2886-91
references.pmid: 12218101
references.citation: J Immunol. 1999 Dec 1;163(11):5954-63
references.pmid: 10570282
references.citation: AIDS Rev. 2003 Oct-Dec;5(4):245-52
references.pmid: 15012003
references.citation: Nature. 1993 Jul 1;364(6432):33-9
references.pmid: 8316295
references.citation: Cell. 1996 Jun 28;85(7):1149-58
references.pmid: 8674120
references.citation: J Immunol. 2007 Jun 15;178(12):8002-12
references.pmid: 17548637
references.citation: J Immunol. 1994 Apr 1;152(7):3282-93
references.pmid: 7511642
references.citation: J Biol Chem. 1987 Jun 25;262(18):8748-58
references.pmid: 3036826
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: Mol Biol Rep. 2009 Jan;36(1):97-103
references.pmid: 18060517
references.citation: Exp Cell Res. 2003 May 15;286(1):96-101
references.pmid: 12729798
references.citation: J Immunol. 2009 Jan 1;182(1):171-82
references.pmid: 19109148
references.citation: J Immunol. 2005 Sep 15;175(6):3594-602
references.pmid: 16148103
references.citation: J Immunol. 2007 Sep 1;179(5):3026-34
references.pmid: 17709517
references.citation: J Intern Med. 2009 Jan;265(1):97-109
references.pmid: 19093963
references.citation: Nat Immunol. 2001 Aug;2(8):698-704
references.pmid: 11477405
references.citation: Cell. 1981 Jun;24(3):625-37
references.pmid: 6788376
references.citation: Immunity. 2002 Oct;17(4):473-85
references.pmid: 12387741
references.citation: J Biol Chem. 1993 Nov 15;268(32):23933-9
references.pmid: 8226933
references.citation: Biometrics. 1982 Dec;38(4):963-74
references.pmid: 7168798
references.citation: Diabetes. 2002 Aug;51(8):2489-95
references.pmid: 12145162
references.citation: Curr Opin Immunol. 2006 Aug;18(4):399-405
references.pmid: 16753288
references.citation: Ann N Y Acad Sci. 1996 Oct 31;795:36-40
references.pmid: 8958915
references.citation: J Immunol. 2005 Sep 1;175(5):3060-6
references.pmid: 16116194
references.citation: EMBO J. 1988 Jul;7(7):1989-94
references.pmid: 3138110
references.citation: Nat Immunol. 2001 Dec;2(12):1174-82
references.pmid: 11694881
references.citation: Immunity. 2010 Aug 27;33(2):254-65
references.pmid: 20691614
references.citation: Genes Immun. 2000;1(4):288-9
references.pmid: 11196706
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D263-6
references.pmid: 18055500
references.citation: J Clin Invest. 2007 Nov;117(11):3148-54
references.pmid: 17975656
references.citation: Nature. 2006 Mar 23;440(7083):540-4
references.pmid: 16525420
references.citation: FEBS Lett. 2009 Jul 7;583(13):2171-8
references.pmid: 19524571
references.citation: PLoS Pathog. 2010 Jan 29;6(1):e1000747
references.pmid: 20126441
references.citation: J Clin Invest. 1999 Mar;103(6):807-15
references.pmid: 10079101
references.citation: N Engl J Med. 2008 Oct 2;359(14):1429-41
references.pmid: 18832244
references.citation: J Biol Chem. 2001 Oct 5;276(40):37472-81
references.pmid: 11438522
references.citation: J Biol Chem. 2004 Dec 31;279(53):55609-17
references.pmid: 15489234
references.citation: Virology. 1998 Jun 20;246(1):113-24
references.pmid: 9656999
references.citation: J Immunol. 2006 Jul 1;177(1):341-54
references.pmid: 16785530
references.citation: Arthritis Rheum. 2001 Dec;44(12):2750-60
references.pmid: 11762935
references.citation: Blood. 2010 Aug 5;116(5):748-58
references.pmid: 20484087
references.citation: J Biol Chem. 2003 Oct 17;278(42):40764-70
references.pmid: 12904296
references.citation: J Immunol. 2002 Mar 15;168(6):2729-36
references.pmid: 11884439
references.citation: J Virol. 2000 Feb;74(3):1209-23
references.pmid: 10627531
references.citation: J Exp Med. 1987 Nov 1;166(5):1351-61
references.pmid: 3500259
references.citation: J Clin Immunol. 2001 Mar;21(2):116-25
references.pmid: 11332650
references.citation: Nature. 2006 Jul 20;442(7100):299-302
references.pmid: 16855590
references.citation: Science. 1999 Dec 3;286(5446):1954-7
references.pmid: 10583958
references.citation: Ann Transplant. 2009 Jul-Sep;14(3):36-44
references.pmid: 19644158
references.citation: Cell. 1996 Jul 26;86(2):233-42
references.pmid: 8706128
references.citation: J Virol. 1997 Sep;71(9):6509-16
references.pmid: 9261370
references.citation: Biochem Biophys Res Commun. 2003 Mar 21;302(4):735-42
references.pmid: 12646231
references.citation: Oncogene. 1999 Mar 4;18(9):1663-76
references.pmid: 10208428
references.citation: J Infect Dis. 2010 Feb 15;201(4):590-9
references.pmid: 20064072
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14002-7
references.pmid: 8943050
references.citation: J Immunol. 1995 Sep 1;155(5):2311-7
references.pmid: 7650367
references.citation: J Immunol. 2010 Jun 1;184(11):6060-6
references.pmid: 20427763
references.citation: Cell Cycle. 2009 Sep 15;8(18):2871-6
references.pmid: 19657229
references.citation: J Biol Chem. 1992 Dec 15;267(35):25589-96
references.pmid: 1460054
references.citation: J Biol Chem. 2008 Mar 21;283(12):7921-35
references.pmid: 18195016
references.citation: J Exp Med. 2004 May 17;199(10):1305-15
references.pmid: 15136591
references.citation: J Clin Invest. 2009 Dec;119(12):3556-72
references.pmid: 19959874
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15137-42
references.pmid: 11752460
references.citation: J Biol Chem. 2006 Apr 14;281(15):10073-80
references.pmid: 16484229
references.citation: J Clin Invest. 2008 Jun;118(6):2039-49
references.pmid: 18497876
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2582-6
references.pmid: 11226282
references.citation: J Cell Physiol. 2000 Mar;182(3):311-22
references.pmid: 10653597
references.citation: J Infect Dis. 2008 Nov 1;198(9):1345-52
references.pmid: 18771406
references.citation: J Immunol. 2009 Jul 15;183(2):890-6
references.pmid: 19561102
references.citation: Blood. 2007 Feb 1;109(3):1069-76
references.pmid: 17003371
references.citation: J Biol Chem. 2004 Nov 12;279(46):47906-11
references.pmid: 15371451
references.citation: J Infect Dis. 2010 May 15;201(10):1481-7
references.pmid: 20377413
references.citation: J Virol. 1997 Apr;71(4):2705-14
references.pmid: 9060623
references.citation: J Biol Chem. 2008 Jun 20;283(25):16971-84
references.pmid: 18426802
references.citation: Mol Cell Biol. 1999 Jun;19(6):4390-404
references.pmid: 10330179
references.citation: Gene. 2001 Feb 7;264(1):87-93
references.pmid: 11245982
references.citation: J Immunol. 2000 Jun 15;164(12):6244-51
references.pmid: 10843677
references.citation: Oncogene. 1999 Sep 16;18(37):5177-86
references.pmid: 10498867
references.citation: Nat Immunol. 2008 Mar;9(3):292-300
references.pmid: 18246069
references.citation: Blood. 2006 May 1;107(9):3447-54
references.pmid: 16391017
references.citation: EMBO J. 1997 Sep 1;16(17):5353-62
references.pmid: 9311995
references.citation: J Leukoc Biol. 2003 Nov;74(5):791-9
references.pmid: 12960247
references.citation: J Biol Chem. 2007 Oct 26;282(43):31289-301
references.pmid: 17823127
references.citation: J Biol Chem. 2004 Oct 15;279(42):43861-9
references.pmid: 15284233
references.citation: Science. 1997 Sep 26;277(5334):1986-90
references.pmid: 9302292
references.citation: Nature. 2005 Apr 28;434(7037):1148-52
references.pmid: 15793562
references.citation: Neurosci Lett. 2009 Aug 21;460(1):66-71
references.pmid: 19446606
references.citation: J Immunol. 2010 Jul 15;185(2):842-55
references.pmid: 20548029
references.citation: J Biol Chem. 2007 Feb 16;282(7):4669-4680
references.pmid: 17164250
references.citation: Cell Death Differ. 2004 Dec;11(12):1299-308
references.pmid: 15332117
references.citation: Cell Regul. 1989 Nov;1(1):27-35
references.pmid: 2519615
references.citation: Immunogenetics. 2000 Apr;51(4-5):281-8
references.pmid: 10803840