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.

Abstract

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.

• Authors: Sunil Kannanganat, Linda S Wyatt, Sailaja Gangadhara, Venkatesarlu Chamcha, Lynette S Chea, Pamela A Kozlowski, Celia C LaBranche, Lakshmi Chennareddi, Benton Lawson, Pradeep B J Reddy, Tiffany M Styles, Thomas H Vanderford, David C Montefiori, Bernard Moss, Harriet L Robinson, Rama Rao Amara
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 197 Issue 9 Pg. 3586-3596 (11 01 2016) ISSN: 1550-6606 [Electronic] United States
• PMID: 27683750 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• Antibodies, Viral
• Immunoglobulin G
• MVA vaccine
• Proteins
• SAIDS Vaccines
• Vaccines, DNA
• Viral Envelope Proteins
• Viral Vaccines
• Granulocyte-Macrophage Colony-Stimulating Factor
• TRIM5(alpha) protein, rhesus monkey
• Ubiquitin-Protein Ligases

Topics

• Animals
• Antibodies, Viral (blood)
• Antibody Formation
• Genotype
• Granulocyte-Macrophage Colony-Stimulating Factor (genetics, immunology)
• Humans
• Immunoglobulin G (metabolism)
• Macaca mulatta
• Proteins (genetics)
• Rectum (immunology)
• SAIDS Vaccines (immunology)
• Simian Acquired Immunodeficiency Syndrome (prevention & control)
• Simian Immunodeficiency Virus (immunology)
• Ubiquitin-Protein Ligases
• Vaccines, DNA
• Vaccinia (immunology)
• Viral Envelope Proteins (immunology)
• Viral Vaccines (immunology)