Functional Roles and Host Interactions of Orthoflavivirus Non-Structural Proteins During Replication

Orthoflavivirus, a genus encompassing arthropod-borne, positive-sense, single-stranded RNA viruses in the Flaviviridae family, represents clinically relevant viruses that pose significant threats to human and animal health worldwide. With warming climates and persistent urbanization, arthropod vectors and the viruses they transmit continue to widen their geographic distribution, expanding endemic zones. Flaviviruses such as dengue virus, Zika virus, West Nile virus, and tick-borne encephalitis virus cause debilitating and fatal infections globally. In 2024, the World Health Organization and the Pan American Health Organization declared the current dengue situation a Multi-Country Grade 3 Outbreak, the highest level. FDA-approved treatment options for diseases caused by flaviviruses are limited or non-existent, and vaccines are suboptimal for many flaviviruses. Understanding the molecular characteristics of the flavivirus life cycle, virus-host interactions, and resulting pathogenesis in various cells and model systems is critical for developing effective therapeutic intervention strategies. This review will focus on the virus-host interactions of mosquito- and tick-borne flaviviruses from the virus replication and assembly perspective, emphasizing the interplay between viral non-structural proteins and host pathways that are hijacked for their advantage. Highlighting interaction pathways, including innate immunity, intracellular movement, and membrane modification, emphasizes the need for rigorous and targeted antiviral research and development against these re-emerging viruses.