ABSTRACT Innate immune recognition of microbial compounds by pattern recognition receptors (PRRs) represents a central regulatory checkpoint in the control of adaptive immune responses. Rig-I-like receptors (RLRs) comprise a PRR family that includes the RNA helicases RIG-I and MDA-5. RLRs recognize microbial RNA species in the cytosol and rely on the essential signaling adaptor MAVS for the induction of the cellular response. RLRs are important mediators of innate immunity to multiple viral infections. However, the role of RLRs in the regulation of adaptive immunity is still poorly understood. MAVS-deficient mice infected with West Nile Virus (WNV) fail to develop an effective virus-specific neutralizing antibody response, suggesting an important role for MAVS signaling in the control of humoral immunity. Here, we will employ a single-round-of-infection mutant of WNV to probe the central hypothesis that RLRs regulate the quality control of the antibody response. Our study will therefore address fundamental mechanistic questions about the role of RLRs in the adaptive immune response to WNV and other RNA viruses. Such insights will advance the development of novel vaccine strategies against WNV and related flaviviruses.