Structural and biochemical insights into flavivirus proteins.

Abstract Flaviviruses are the fastest spreading arthropod-borne viruses that cause severe symptoms such as hepatitis, hemorrhagic fever, encephalitis, and congenital deformities. Nearly 40% of the entire human population is at risk of flavivirus epidemics. Yet, effective vaccination is restricted only to a few flaviviruses such as yellow fever and Japanese encephalitis viruses, and most recently for select cases of dengue virus infections. Despite the global spread of dengue virus, and emergence of new threats such as Zika virus and a new genotype of Japanese encephalitis virus, insights into flavivirus targets for potentially broad-spectrum vaccination are limited. Flaviviruses such as dengue, yellow fever, Zika, and West Nile viruses cause a wide variety of symptoms in humans ranging from a mild fever to liver damage, severe hemorrhagic disease, and permanent neurological defects. Current understanding of viral properties that are determinants of host interactions is limited, which in turn has restricted the development of broad-spectrum anti-virals. In this review article, we highlight biochemical and structural differences in flavivirus proteins critical for virus assembly and host interactions. A comparative sequence analysis of pH-responsive properties of viral structural proteins identifies trends in conservation of complementary acidic-basic character between interacting viral structural proteins. This is highly relevant to the understanding of pH-sensitive differences in virus assembly in organelles such as neutral ER and acidic Golgi. Surface residues in viral interfaces identified by structural approaches are shown to demonstrate partial conservation, further reinforcing virus-specificity in assembly and interactions with host proteins. A comparative analysis of epitope conservation in emerging flaviviruses identifies therapeutic antibody candidates that have potential as broad spectrum anti-virals, thus providing a path towards development of vaccines.