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The journal of immunology : official journal of the American Association of Immunologists v.197 no.9, 2016년, pp.3586 - 3596   SCI SCIE
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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

Kannanganat, Sunil (Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329 ); Wyatt, Linda S. (Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 ); Gangadhara, Sailaja (Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329 ); Chamcha, Venkatesarlu (Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329 ); Chea, Lynette S. (Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329 ); Kozlowski, Pamela A. (Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112 ); LaBranche, Celia C. (Department of Surgery, Duke University Medical Center, Durham, NC 27705 ); Chennareddi, Lakshmi (and ); Lawson, Benton (Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329 ); Reddy, Pradeep B. J. (Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329 ); Styles, Tiffany M. (Emory Vaccine Center, Yerkes National ); Vanderford, Thomas H. ( ); Montefiori, David C. ( ); Moss, Bernard ( ); Robinson, Harriet L. ( ); Amara, Rama Rao ( );
  • 초록  

    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 × 10 5 PFU) 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.


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