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West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant has several features for an ideal vaccine candidate, including significantly reduced neuroinvasiveness, induction of strong adaptive immunity, and protection of mice from wild-type (WT) WNV infection. Here, we determined the role of mitochondrial antiviral signaling protein (MAVS), the adaptor protein for RIG-I-like receptor in regulating host immunity against the NS4B-P38G vaccine. We found that<jats:italic>Mavs<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice were more susceptible to NS4B-P38G priming than WT mice.<jats:italic>Mavs<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice had a transiently reduced production of antiviral cytokines and an impaired CD4<jats:sup>+<\/jats:sup>T cell response in peripheral organs. However, antibody and CD8<jats:sup>+<\/jats:sup>T cell responses were minimally affected. NS4B-P38G induced lower type I interferon (IFN), IFN-stimulating gene, and proinflammatory cytokine responses in<jats:italic>Mavs<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>dendritic cells and subsequently compromised the antigen-presenting capacity for CD4<jats:sup>+<\/jats:sup>T cells. Interestingly,<jats:italic>Mavs<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice surviving NS4B-P38G priming were all protected from a lethal WT WNV challenge. NS4B-P38G-primed<jats:italic>Mavs<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice exhibited equivalent levels of protective CD4<jats:sup>+<\/jats:sup>T cell recall response, a modestly reduced WNV-specific IgM production, but more robust CD8<jats:sup>+<\/jats:sup>T cell recall response. Taken together, our results suggest that MAVS is essential for boosting optimal primary CD4<jats:sup>+<\/jats:sup>T cell responses upon NS4B-P38G vaccination and yet is dispensable for host protection and recall T cell responses during secondary WT WNV infection.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The production of innate cytokines induced by the recognition of pathogen recognition receptors (PRRs) via their cognate ligands are critical for enhancing antigen-presenting cell functions and influencing T cell responses during microbial infection. The use of PRR agonists and the underlying molecular mechanisms have been the major focus in individual vaccine development. Here, we determined the role of mitochondrial antiviral-signaling protein (MAVS), the adaptor protein for RIG-I like receptor in regulating host immunity against the live attenuated West Nile virus (WNV) vaccine strain, the nonstructural (NS) 4B-P38G mutant. We found that MAVS is important for boosting optimal primary CD4<jats:sup>+<\/jats:sup>T cell response during NS4B-P38G vaccination. However, MAVS is dispensable for memory T cell development and host protection during secondary wild-type WNV infection. Overall, these results may be utilized as a paradigm to aid in the rational development of other efficacious live attenuated flavivirus vaccines.<\/jats:p>","DOI":"10.1128\/jvi.02097-16","type":"journal-article","created":{"date-parts":[[2017,1,12]],"date-time":"2017-01-12T02:32:08Z","timestamp":1484188328000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["MAVS Is Essential for Primary CD4<sup>+<\/sup>T Cell Immunity but Not for Recall T Cell Responses following an Attenuated West Nile Virus Infection"],"prefix":"10.1128","volume":"91","author":[{"given":"Huanle","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evandro","family":"Winkelmann","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, 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