Cellular receptors and host factors mediating orthoflavivirus entry

Orthoflaviviruses are positive-sense, enveloped RNA viruses that include dengue virus (DENV), Zika virus (ZIKV), yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). Viral entry is a multistep process governed by the envelope (E) glycoprotein, virion lipid composition, and host-cell molecules that act at distinct mechanistic stages. A major limitation of the current literature is that attachment factors, internalization receptors, immune-modulatory receptors, and membrane-associated cofactors are often collectively termed "receptors", which can obscure the strength and interpretation of the underlying evidence. This review therefore reorganizes reported orthoflavivirus entry-associated molecules into four functional classes: attachment factors, bona fide or candidate internalization receptors, indirect immune-modulatory receptors, and membrane-associated or post-entry cofactors. We place particular emphasis on DENV because it imposes a major clinical burden among orthoflaviviruses and has been the subject of the most extensive receptor-related research. By integrating evidence from binding assays, genetic loss-of-function studies, and in vivo models, this review highlights conserved and virus-specific entry mechanisms. This mechanism-based framework may guide the development of receptor decoys and host-targeting antivirals, although clinical translation will require rigorous validation of antiviral breadth, delivery, safety, and resistance potential.