The flavivirus genus includes the medically important arboviruses dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBE), among others. Flavivi-ruses are enveloped viruses with a single-stranded, 10.7 kb, positive-sense RNA genome that has a type I 5' cap but no poly(A) tail (Chambers et al 1990). The genomic RNA is translated as a single polyprotein, which is then cleaved into three structural proteins (C, prM/M, E) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) by both viral and host proteases (Fig. 1A). Hydrophobic amino acids preceding the N-termini of prM, E, NS1 and NS4B are
thought to serve as signal sequences for insertion of these proteins into the endoplasmic reticulum (ER) membrane. Cleavage at the N-terminus of the signal sequence for NS4B, which is located in NS4A, generates a 23-amino acid peptide known as 2K (Lin et al 1993). The NS proteins include an RNA-dependent RNA polymerase (RdRp; NS5), a helicase/protease (NS3), and other proteins that form part of the viral replication complex (Khromykh et al 1999, 2000, Lindenbach & Rice 2001). For flaviviruses in general, it is thought that the envelope protein E interacts with a cellular receptor and that viral uptake occurs via receptor-mediated endocytosis (Lindenbach & Rice 2001). Endosome acidification leads to fusion of the viral and endosomal membranes and release of the nucleocapsid into the cytoplasm (Heinz et al 1994a, 1994b). At the ER membrane, the structural proteins and NS1 undergo co-translational translocation and membrane-associated cleavage, whereas the remainder of the NS proteins do not translocate though the ER membrane and remain in the cytoplasm (Falgout & Markoff 1995, Markoff et al 1994). As infection proceeds, virus-induced hypertrophy of intracellular membranes occurs, and vesicle packets thought to be sites of viral replication accumu late (Mackenzie et al 1999). Virus assembly takes place at these membranes, and viral particles pass through the Golgi, where modifications to E and M occur, and are exocytosed via secretory vesicles (Heinz et al 1994a).
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