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
| Autor: | Linda S. Wyatt, Lynette S. Chea, Rama Rao Amara, Lakshmi Chennareddi, Thomas H. Vanderford, Benton Lawson, Bernard Moss, Pamela A. Kozlowski, Harriet L. Robinson, Pradeep B. J. Reddy, Venkatesarlu Chamcha, Sunil Kannanganat, Sailaja Gangadhara, Tiffany M. Styles, Celia C. LaBranche, David C. Montefiori |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Modified vaccinia Ankara Genotype Ubiquitin-Protein Ligases viruses Immunology Simian Acquired Immunodeficiency Syndrome Antibodies Viral medicine.disease_cause complex mixtures Macaque Article Virus Immunoglobulin G 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Viral Envelope Proteins biology.animal Vaccines DNA Vaccinia medicine Animals Humans Immunology and Allergy Avidity biology Immunogenicity Rectum SAIDS Vaccines Granulocyte-Macrophage Colony-Stimulating Factor Proteins Viral Vaccines Simian immunodeficiency virus Macaca mulatta Virology 030104 developmental biology chemistry 030220 oncology & carcinogenesis Antibody Formation biology.protein Simian Immunodeficiency Virus |
| Zdroj: | The Journal of Immunology. 197:3586-3596 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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 × 105 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. |
| Databáze: | OpenAIRE |
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