High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5α-Restrictive Macaques.
We tested, in rhesus macaques, the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/SIV macaque 239 vaccine. High doses of MVA/GM-CSF did not affect the levels of systemic envelope (Env)-specific Ab, but it did decrease the expression of the gut-homing receptor α4β7 on plasmacytoid dendritic cells (p < 0.01) and the magnitudes of Env-specific IgA (p = 0.01) and IgG (p < 0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus macaques subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus SIVsmE660. Eight of nine TRIM5α-restrictive animals receiving no or the lowest dose (1 × 105PFU) of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group, only 1 of 12 animals resisted all 12 challenges. In the TRIM5α-restrictive animals, but not in the TRIM5α-permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r = +0.6) and IgA (r = +0.6), the avidity of Env-specific serum IgG (r = +0.5), and Ab dependent cell-mediated virus inhibition (r = +0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that 1) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of TRIM5α restriction, 2) nonneutralizing Ab responses contribute to protection against SIVsmE660 in TRIM5α-restrictive animals, and 3) high doses of codelivered MVA/GM-CSF inhibit mucosal Ab responses and the protection elicited by MVA expressing noninfectious SIV macaque 239 virus-like particles.
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Sunil
S
Kannanganat
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Linda S
LS
Wyatt
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Sailaja
0000-0001-8603-628X
S
Gangadhara
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Venkatesarlu
V
Chamcha
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Lynette S
LS
Chea
Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112.
Pamela A
PA
Kozlowski
Department of Surgery, Duke University Medical Center, Durham, NC 27705; and.
Celia C
CC
LaBranche
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Lakshmi
L
Chennareddi
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Benton
B
Lawson
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Pradeep B J
PB
Reddy
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Tiffany M
TM
Styles
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Thomas H
TH
Vanderford
Department of Surgery, Duke University Medical Center, Durham, NC 27705; and.
David C
0000-0003-0856-6319
DC
Montefiori
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Bernard
0000-0002-2154-8564
B
Moss
GeoVax, Inc., Smyrna, GA 30080 hrobinson@geovax.com ramara@emory.edu.
Harriet L
0000-0001-6380-3458
HL
Robinson
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; hrobinson@geovax.com ramara@emory.edu.|Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322.
Rama Rao
0000-0002-6309-6797
RR
Amara
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D005838:Genotype; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008253:Macaca mulatta; D011506:Proteins / Q000235:genetics; D012007:Rectum / Q000276:immunology*; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D044767:Ubiquitin-Protein Ligases; D019444:Vaccines, DNA; D014615:Vaccinia / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*
D000914:Antibodies, Viral; D007074:Immunoglobulin G; C560489:MVA vaccine; D011506:Proteins; D018449:SAIDS Vaccines; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases
J Immunol. 2004 Mar 15;172(6):3745-57
15004179
J Virol. 2006 Aug;80(15):7676-87
16840346
Methods. 1997 Aug;12(4):288-93
9245608
J Immunol. 2007 May 15;178(10):6596-603
17475891
Gene Ther. 2001 Jul;8(13):1011-23
11438836
J Immunol. 2000 Mar 15;164(6):3102-11
10706700
J Clin Oncol. 2007 Jun 20;25(18):2546-53
17577033
J Virol. 2014 May;88(10):5864-9
24574408
Int Immunol. 2009 Apr;21(4):361-77
19190084
Nature. 2004 Feb 26;427(6977):848-53
14985764
J Immunol. 1998 Sep 1;161(5):2325-32
9725227
J Virol. 2005 Apr;79(7):4043-54
15767406
Open Forum Infect Dis. 2016 Feb 11;3(1):ofw034
27006959
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7465-70
16648264
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
8097319
Sci Transl Med. 2015 Oct 21;7(310):310rv7
26491081
PLoS Biol. 2010 Aug 24;8(8):
20808775
Nature. 1998 Mar 19;392(6673):245-52
9521319
Virology. 1995 Jun 1;209(2):569-79
7778289
Nature. 2014 Jan 23;505(7484):502-8
24352234
Virology. 2006 Sep 1;352(2):285-94
16740288
J Infect Dis. 2014 Jul 1;210(1):99-110
24403557
J Exp Med. 1992 Dec 1;176(6):1693-702
1460426
J Exp Med. 2009 May 11;206(5):1117-34
19414559
Immunity. 2004 Oct;21(4):527-38
15485630
J Immunol. 2000 Oct 1;165(7):3772-81
11034382
Vaccine. 2012 Jun 13;30(28):4233-9
22537983
J Immunol. 1997 Nov 15;159(10):5107-13
9366440
Sci Transl Med. 2011 May 4;3(81):81ra36
21543722
In Vitro Cell Dev Biol Anim. 1995 Mar;31(3):196-206
7757302
J Immunol. 2010 Dec 15;185(12):7262-73
21076059
J Virol. 2010 Sep;84(18):9190-9
20592091
J Interferon Cytokine Res. 1999 Jan;19(1):77-84
10048771
J Virol. 2011 Sep;85(18):9637-40
21734037
J Immunol. 2002 Jan 15;168(2):562-8
11777947
Ann Oncol. 2007 Feb;18(2):226-32
17116643
Vaccine. 2012 Feb 21;30(9):1737-45
22178526
Virology. 2007 Dec 5;369(1):153-67
17698160
J Med Primatol. 2005 Oct;34(5-6):303-12
16128925
Cancer Res. 2004 Sep 1;64(17):6337-43
15342423
J Virol. 2011 Oct;85(19):10389-98
21775457
Infect Immun. 2002 Feb;70(2):584-90
11796586
J Virol. 2014 Feb;88(3):1809-14
24257612
Cytokine Growth Factor Rev. 2002 Apr;13(2):185-93
11900993
J Virol. 2009 Mar;83(6):2686-96
19129440
J Infect Dis. 2011 Jul 1;204(1):164-73
21628671
J Acquir Immune Defic Syndr. 2000 Aug 1;24(4):297-309
11015145
J Virol. 2014 Sep 1;88(17):9579-89
24920805
Growth Factors. 2004 Dec;22(4):225-31
15621725
Semin Oncol. 1996 Feb;23(1):135-47
8607023
Curr Protoc Immunol. 2005 Jan;Chapter 12:12.11.1-12.11.17
18432938