Figure 1.

Schematic of the flavivral lifecycle. The Flaviviral lifecycle starts with the (1) internalization of the virion by attachment and receptor-mediated endocytosis. (2) Under the mildly acidic environment of the endosome, the viral membrane fuses with that of the endosomal membrane, uncoats and the nucleocapsid is released into the cytoplasm. (3) In the cytoplasm, vRNA is translated into a polyprotein by the host translational machinery and inserted into the ER membrane. The polyprotein is subsequently cleaved by host and viral proteins to generate 3 structural proteins and at least 7 non-structural proteins. (4) These non-structural proteins form the viral replication complex. After initial viral replication, the viral proteins assist in generating Replication Organelles (RO) and vesicle packets (VP) in the ER shielding the virus from the cytoplasm. In the RO, +ssRNA is generated and transported to another invagination in the ER, the assembly site, the VP. (5) For encapsidation of the +ssRNA, capsid protein accumulates and complexes on lipid droplets (LD) and is recruited to the VP alongside the +ssRNA. Heterodimers of prM and E are recruited to the VP and trimerize on the membrane. Subsequently the VP can bud into the ER forming an immature virion. (6) Virions accumulate in ER cisternae before transport for maturation through the GBF1-dependent host secretory pathway or through secretory autophagy. (7) The virus can be released as free virions or additionally, in membrane enclosed forms derived from autophagosomes, in a host-derived lipid bilayer as quasispecies