title: Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques.
abstract: Adjuvant effects on innate as well as adaptive immunity may be critical for inducing protection against mucosal HIV and simian immunodeficiency virus (SIV) exposure. We therefore studied effects of Toll-like receptor agonists and IL-15 as mucosal adjuvants on both innate and adaptive immunity in a peptide/poxvirus HIV/SIV mucosal vaccine in macaques, and made three critical observations regarding both innate and adaptive correlates of protection: (i) adjuvant-alone without vaccine antigen impacted the intrarectal SIVmac251 challenge outcome, correlating with surprisingly long-lived APOBEC3G (A3G)-mediated innate immunity; in addition, even among animals receiving vaccine with adjuvants, viral load correlated inversely with A3G levels; (ii) a surprising threshold-like effect existed for vaccine-induced adaptive immunity control of viral load, and only antigen-specific polyfunctional CD8(+) T cells correlated with protection, not tetramer(+) T cells, demonstrating the importance of T-cell quality; (iii) synergy was observed between Toll-like receptor agonists and IL-15 for driving adaptive responses through the up-regulation of IL-15Ralpha, which can present IL-15 in trans, as well as for driving the innate A3G response. Thus, strategic use of molecular adjuvants can provide better mucosal protection through induction of both innate and adaptive immunity.
authors.affiliation: Vaccine Branch, Biostatistics and Data Management Section, and Laboratory of Experimental Immunology, National Cancer Institute, and Laboratory of Host Defenses and Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA. suiy@mail.nih.gov
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Sui
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Susan
authors.initials: S
authors.lastname: Gagnon
authors.forename: Amiran
authors.initials: A
authors.lastname: Dzutsev
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: Monica
authors.initials: M
authors.lastname: Vaccari
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.forename: Dennis
authors.initials: D
authors.lastname: Klinman
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
authors.forename: Brian
authors.initials: B
authors.lastname: Kelsall
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.forename: Igor M
authors.initials: IM
authors.lastname: Belyakov
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control* / Q000635:transmission; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019409:Interleukin-15; D018449:SAIDS Vaccines; D051193:Toll-Like Receptors; D003564:Cytidine Deaminase
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15154-9
references.pmid: 15477598
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16260-5
references.pmid: 18845682
references.citation: Cell. 2003 Jun 13;113(6):803-9
references.pmid: 12809610
references.citation: Nat Med. 2001 Dec;7(12):1320-6
references.pmid: 11726972
references.citation: Nat Immunol. 2006 May;7(5):507-16
references.pmid: 16617337
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5201-6
references.pmid: 18362335
references.citation: J Immunol. 2008 Apr 15;180(8):5439-47
references.pmid: 18390726
references.citation: J Virol. 2005 Jul;79(13):8480-92
references.pmid: 15956591
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18648-53
references.pmid: 18000037
references.citation: J Exp Med. 2006 Apr 17;203(4):865-70
references.pmid: 16606671
references.citation: J Exp Med. 2006 Dec 25;203(13):2887-93
references.pmid: 17145955
references.citation: J Immunol. 2007 Jun 1;178(11):7211-21
references.pmid: 17513770
references.citation: J Virol. 2005 Sep;79(17):11513-6
references.pmid: 16103203
references.citation: Nat Protoc. 2006;1(3):1507-16
references.pmid: 17406442
references.citation: Blood. 2006 Apr 15;107(8):3258-64
references.pmid: 16373659
references.citation: Nat Med. 2008 Oct;14(10):1077-87
references.pmid: 18806803
references.citation: Cytokine. 2001 Dec 7;16(5):191-204
references.pmid: 11814315
references.citation: Nature. 2009 Jan 1;457(7225):87-91
references.pmid: 18997770
references.citation: J Infect Dis. 2007 Apr 1;195(7):960-4
references.pmid: 17330785
references.citation: Lancet. 2008 Nov 29;372(9653):1894-1905
references.pmid: 19012957
references.citation: J Exp Med. 2007 Oct 29;204(11):2733-46
references.pmid: 17954572
references.citation: J Virol. 2001 Nov;75(22):10958-68
references.pmid: 11602736
references.citation: Gastroenterology. 2009 May;136(6):1965-78
references.pmid: 19462506
references.citation: Science. 1999 Nov 12;286(5443):1353-7
references.pmid: 10558989
references.citation: J Virol. 2004 Mar;78(5):2212-21
references.pmid: 14963117
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15831-6
references.pmid: 19717425
references.citation: Nat Med. 2007 Jan;13(1):46-53
references.pmid: 17173051
references.citation: Nat Immunol. 2004 Oct;5(10):987-95
references.pmid: 15454922
references.citation: Nat Rev Immunol. 2006 Aug;6(8):595-601
references.pmid: 16868550
references.citation: J Virol. 2009 Sep;83(18):9474-85
references.pmid: 19587057
references.citation: J Exp Med. 2004 Sep 20;200(6):749-59
references.pmid: 15365096
references.citation: J Virol. 2009 Jan;83(2):884-95
references.pmid: 19004943
references.citation: J Clin Invest. 2010 Feb;120(2):607-16
references.pmid: 20101095
references.citation: J Immunol. 2007 Feb 1;178(3):1671-9
references.pmid: 17237417
references.citation: J Virol. 2008 Oct;82(19):9629-38
references.pmid: 18667509
references.citation: J Biol Chem. 2007 Feb 9;282(6):3539-46
references.pmid: 17110377
references.citation: Vaccine. 2009 Feb 5;27(6):870-81
references.pmid: 19084567
references.citation: J Virol. 2005 Dec;79(24):15556-66
references.pmid: 16306626
references.citation: J Exp Med. 2006 May 15;203(5):1249-58
references.pmid: 16636134
references.citation: J Immunol. 2005 Jul 1;175(1):112-23
references.pmid: 15972637
references.citation: PLoS One. 2008 Jul 23;3(7):e2745
references.pmid: 18648514
references.citation: J Virol. 2006 May;80(10):5074-7
references.pmid: 16641299
references.citation: Nature. 2005 May 5;435(7038):108-14
references.pmid: 15829920