Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques.
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.
Sui
Yongjun
Y
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
Zhu
Qing
Q
Gagnon
Susan
S
Dzutsev
Amiran
A
Terabe
Masaki
M
Vaccari
Monica
M
Venzon
David
D
Klinman
Dennis
D
Strober
Warren
W
Kelsall
Brian
B
Franchini
Genoveffa
G
Belyakov
Igor M
IM
Berzofsky
Jay A
JA
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
D000276:Adjuvants, Immunologic; D019409:Interleukin-15; D018449:SAIDS Vaccines; D051193:Toll-Like Receptors; D003564:Cytidine Deaminase
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15154-9
15477598
Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16260-5
18845682
Cell. 2003 Jun 13;113(6):803-9
12809610
Nat Med. 2001 Dec;7(12):1320-6
11726972
Nat Immunol. 2006 May;7(5):507-16
16617337
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5201-6
18362335
J Immunol. 2008 Apr 15;180(8):5439-47
18390726
J Virol. 2005 Jul;79(13):8480-92
15956591
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18648-53
18000037
J Exp Med. 2006 Apr 17;203(4):865-70
16606671
J Exp Med. 2006 Dec 25;203(13):2887-93
17145955
J Immunol. 2007 Jun 1;178(11):7211-21
17513770
J Virol. 2005 Sep;79(17):11513-6
16103203
Nat Protoc. 2006;1(3):1507-16
17406442
Blood. 2006 Apr 15;107(8):3258-64
16373659
Nat Med. 2008 Oct;14(10):1077-87
18806803
Cytokine. 2001 Dec 7;16(5):191-204
11814315
Nature. 2009 Jan 1;457(7225):87-91
18997770
J Infect Dis. 2007 Apr 1;195(7):960-4
17330785
Lancet. 2008 Nov 29;372(9653):1894-1905
19012957
J Exp Med. 2007 Oct 29;204(11):2733-46
17954572
J Virol. 2001 Nov;75(22):10958-68
11602736
Gastroenterology. 2009 May;136(6):1965-78
19462506
Science. 1999 Nov 12;286(5443):1353-7
10558989
J Virol. 2004 Mar;78(5):2212-21
14963117
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15831-6
19717425
Nat Med. 2007 Jan;13(1):46-53
17173051
Nat Immunol. 2004 Oct;5(10):987-95
15454922
Nat Rev Immunol. 2006 Aug;6(8):595-601
16868550
J Virol. 2009 Sep;83(18):9474-85
19587057
J Exp Med. 2004 Sep 20;200(6):749-59
15365096
J Virol. 2009 Jan;83(2):884-95
19004943
J Clin Invest. 2010 Feb;120(2):607-16
20101095
J Immunol. 2007 Feb 1;178(3):1671-9
17237417
J Virol. 2008 Oct;82(19):9629-38
18667509
J Biol Chem. 2007 Feb 9;282(6):3539-46
17110377
Vaccine. 2009 Feb 5;27(6):870-81
19084567
J Virol. 2005 Dec;79(24):15556-66
16306626
J Exp Med. 2006 May 15;203(5):1249-58
16636134
J Immunol. 2005 Jul 1;175(1):112-23
15972637
PLoS One. 2008 Jul 23;3(7):e2745
18648514
J Virol. 2006 May;80(10):5074-7
16641299
Nature. 2005 May 5;435(7038):108-14
15829920