TitleModification of Three Amino Acids in Sodium Taurocholate Cotransporting Polypeptide Renders Mice Susceptible to Infection with Hepatitis D Virus In Vivo
AuthorsHe, Wenhui
Cao, Zhiliang
Mao, Fengfeng
Ren, Bijie
Li, Yunfei
Li, Dan
Li, Huiyu
Peng, Bo
Yan, Huan
Qi, Yonghe
Sun, Yinyan
Wang, Fengchao
Sui, Jianhua
Li, Wenhui
AffiliationPeking Univ, Sch Life Sci, Postdoctoral Program, Beijing, Peoples R China.
Natl Inst Biol Sci, Beijing, Peoples R China.
Beijing Normal Univ, Sch Life Sci, Grad Program, Beijing, Peoples R China.
Tsinghua Univ, Sch Life Sci, Grad Program, Beijing, Peoples R China.
Peking Univ, Sch Life Sci, Grad Program, Beijing, Peoples R China.
Natl Inst Biol Sci, Beijing, Peoples R China.
Li, WH (reprint author), Beijing Normal Univ, Sch Life Sci, Grad Program, Beijing, Peoples R China.
Sui, JH (reprint author), Tsinghua Univ, Sch Life Sci, Grad Program, Beijing, Peoples R China.
Li, WH (reprint author), Peking Univ, Sch Life Sci, Grad Program, Beijing, Peoples R China.
KeywordsDELTA-VIRUS
B-VIRUS
TRANSGENIC MICE
MOLECULAR DETERMINANTS
HUMAN HEPATOCYTES
REPLICATION
LIVER
ENTRY
ADENOSINE
GENOME
Issue Date2016
PublisherJOURNAL OF VIROLOGY
CitationJOURNAL OF VIROLOGY.2016,90(19),8866-8874.
AbstractSodium taurocholate cotransporting polypeptide (NTCP) was identified as a functional receptor for hepatitis D virus (HDV) and its helper hepatitis B virus (HBV). In cultured cell lines, HDV infection through mouse NTCP is restricted by residues 84 to 87 of the receptor. This study shows that mice with these three amino acids altered their corresponding human residues (H84R, T86K, and S87N) in endogenous mouse NTCP support de novo HDV infection in vivo. HDV infection was documented by the presence of replicative forms of HDV RNA and HDV proteins in liver cells at day 6 after viral inoculation. Monoclonal antibody specifically binding to the motif centered on K86 in NTCP partially inhibited HDV infection. These studies demonstrated specific interaction between the receptor and the viral envelopes in vivo and established a novel mouse model with minimal genetic manipulation for studying HDV infection. The model will also be useful for evaluating entry inhibitors against HDV and its helper HBV. IMPORTANCE NTCP was identified as a functional receptor for both HDV and HBV in cell cultures. We recently showed that neonatal C57BL/6 transgenic (Tg) mice exogenously expressing human NTCP (hNTCP-Tg) in liver support transient HDV infection. In this study, we introduced alterations of three amino acids in the endogenous NTCP of FVB mice through genome editing. The mice with the humanized NTCP residues (H84R, T86K, and S87N) are susceptible to HDV infection, and the infection can be established in both neonatal and adult mice with this editing. We also developed a monoclonal antibody specifically targeting the region of NTCP centered on lysine residue 86, and it can differentiate the modified mouse NTCP from that of the wild type and partially inhibited HDV infection. These studies shed new light on NTCP-mediated HDV infection in vivo, and the NTCP-modified mice provide a useful animal model for studying HDV infection and evaluating antivirals against the infection.
URIhttp://hdl.handle.net/20.500.11897/493393
ISSN0022-538X
DOI10.1128/JVI.00901-16
IndexedSCI(E)
PubMed
Appears in Collections:生命科学学院

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