The Many Faces of a Dynamic Virion: Implications of Viral Breathing on Flavivirus Biology and Immunogenicity

Flaviviruses are arthropod-borne RNA viruses that are a significant threat to global health due to their widespread distribution, ability to cause severe disease in humans, and capacity for explosive spread following introduction into new regions. Members of this genus include dengue, tick-borne encephalitis, yellow fever, and Zika viruses. Vaccination has been a highly successful means to control flaviviruses, and neutralizing antibodies are an important component of a protective immune response. High-resolution structures of flavivirus structural proteins and virions, alone and in complex with antibodies, provide a detailed understanding of viral fusion mechanisms and virus-antibody interactions. However, mounting evidence suggests these structures provide only a snapshot of an otherwise structurally dynamic virus particle. The contribution of the structural ensemble arising from viral breathing to the biology, antigenicity, and immunity of flaviviruses is discussed, including implications for the development and evaluation of flavivirus vaccines.