Regulation of Flavivirus RNA synthesis and replication

•Detailed structural models are available for Flavivirus NS5 and NS3 proteins.•Complex structures of NS5 and NS3 with NTP and RNA substrates and regulatory elements are needed.•The precise sequence and in many cases functions of Flavivirus RNA elements are known.•Interaction maps of NS3 and/or NS5 with 5′ and 3′ UTR RNA are within reach.•Future challenges involve deciphering the timing and coordination of RNA synthesis and capping.

RNA synthesis and replication of the members of the Flavivirus genus (including dengue, West Nile and Japanese encephalitis viruses) is regulated by a wide variety of mechanisms and actors. These include the sequestration of the RNA-dependent RNA polymerase (RdRp) for functions other than RNA synthesis, regulatory interactions with other viral and host proteins within the replication complex (RC), and regulatory elements within the RNA genome itself. In this review, we discuss our current knowledge of the multiple levels at which Flavivirus RNA synthesis is controlled. We aim to bring together two active research fields: the structural and functional biology of individual proteins of the RC and the impressive wealth of knowledge acquired regarding the viral genomic RNA.