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<p>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.</p>

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Cellular receptors and host factors mediating orthoflavivirus entry

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月8日

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  • Shuangshuang Yang,
  • Meng Zhang,
  • Xingyong Yang,
  • Jinxi Yue,
  • Xue Li,
  • Peiyue Zhang,
  • Hong Zhang

摘要

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.