title: Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide.
abstract: Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), primarily infect humans, chimpanzees, or tree shrews (Tupaia belangeri). Viral infections in other species are known to be mainly restricted at the entry level since viral replication can be achieved in the cells by transfection of the viral genome. Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for HBV and HDV, and amino acids 157 to 165 of NTCP are critical for viral entry and likely limit viral infection of macaques. However, the molecular determinants for viral entry restriction in mouse NTCP (mNTCP) remain unclear. In this study, mNTCP was found to be unable to support either HBV or HDV infection, although it can bind to pre-S1 of HBV L protein and is functional in transporting substrate taurocholate; comprehensive swapping and point mutations of human NTCP (hNTCP) and mNTCP revealed molecular determinants restricting mNTCP for viral entry of HBV and HDV. Remarkably, when mNTCP residues 84 to 87 were substituted by human counterparts, mNTCP can effectively support viral infections. In addition, a number of cell lines, regardless of their species or tissue origin, supported HDV infection when transfected with hNTCP or mNTCP with residues 84 to 87 replaced by human counterparts, highlighting the central role of NTCP for viral infections mediated by HBV envelope proteins. These studies advance our understanding of NTCP-mediated viral entry of HBV and HDV and have important implications for developing the mouse model for their infections.
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yan
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.forename: Wenhui
authors.initials: W
authors.lastname: He
authors.forename: Guocai
authors.initials: G
authors.lastname: Zhong
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Qi
authors.forename: Bijie
authors.initials: B
authors.lastname: Ren
authors.forename: Zhenchao
authors.initials: Z
authors.lastname: Gao
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Jing
authors.forename: Mei
authors.initials: M
authors.lastname: Song
authors.forename: Guangwei
authors.initials: G
authors.lastname: Xu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sui
authors.forename: Wenhui
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004797:Enzyme-Linked Immunosorbent Assay; D016650:Fluorescein-5-isothiocyanate; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000378:metabolism*; D003698:Hepatitis Delta Virus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013656:Taurocholic Acid / Q000378:metabolism; D014316:Tritium; D014709:Vero Cells; D053586:Virus Internalization
chemical_list: D006514:Hepatitis B Surface Antigens; D029363:Organic Anion Transporters, Sodium-Dependent; D011498:Protein Precursors; D027981:Symporters; C050806:presurface protein 1, hepatitis B surface antigen; D014316:Tritium; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D016650:Fluorescein-5-isothiocyanate