Role of the Dengue Virus 5' and 3' Untranslated Regions in Viral Replication

Abstract

As for all plus-stranded RNA viruses, dengue virus (DENV) genomic RNA is infectious. Transfection of full length DENV RNA genome into a susceptible cell triggers a complete cycle of viral replication. Construction of cDNA clones together with reverse genetics has proven to be a valuable tool to uncover genetic determinants of viral replication and to understand the function of the viral untranslated regions (UTRs). Translation initiation and initiation of RNA synthesis occur at the 5' and 3' terminal regions of the genome, respectively, and rely on complex RNA-RNA and RNA- protein interactions. The DENV 5'UTR contains two defined RNA structures, Stem-Loop A and Stem-Loop B, which have distinct functions during the process of viral RNA synthesis. The viral 3'UTR contains three domains with conserved sequences and structures. In these domains, there are RNA elements that are essential for the replication process and other elements that act as enhancers of the process. The 5' and 3' terminal regions of the viral RNA also carry inverted complementary sequences that mediate long-range RNA-RNA interactions and genome cyclization. It has been demonstrated for dengue and other flaviviruses that the circular conformation of the genome is a crucial determinant for viral replication. In the last few years, a great deal has been learned about the mechanisms by which the viral UTRs function during DENV replication. In this chapter, I discuss the current understanding of the function of different RNA structures of the DENV UTRs and provide some working models of how genome cyclization enables DENV RNA synthesis.