**4. Viral replication**

DENV like other flaviviruses, after adsorption to receptors, is endocytosed by cells in clathrindependent manner and then is further transported to endosomes [42]. However, according to one study, DENV can adopt clathrin-independent pathways as well to gain entry into mammalian cells in particular [43]. DENV nucleocapsid is released into cytosol after acidic pH triggered rearrangements of envelope protein in late endosomes leading to fusion of viral envelope and cellular endosome membrane [44, 45]. The nucleocapsid disassembles, and viral genome is translated by endoplasmic reticulum (ER)-located ribosomes generating numerous copies of viral proteins. NS5 and other viral nonstructural proteins along with various host proteins establish replication complexes [46]. At replication complex, the viral polymerase (NS5) transcribes negative viral RNA, which serves as a template for synthesis of subsequent positive viral RNA copies. Viral replication is regulated by 5′-3' UTR sequences (upstream of AUG region) present in 5′-3' UTRs, which are actively involved in the circularization of DENV RNA [47]. These newly synthesized positive DENV RNAs interact with core proteins to assemble into nucleocapsids [48]. The nucleocapsid buds into ER lumen, thereby getting enveloped in a membrane bilayer carrying the viral prM and E proteins [46]. From ER lumen, immature viral particles are transported through cellular secretary pathways, furin protease cleaves prM, and results in the formation of mature viral particles capable of infecting naïve cells [49].
