title: Biological characteristics of the A1762T/G1764A mutant strain of hepatitis B virus in vivo.
abstract: The double nucleotide, A1762T and G1764A exchange (TA mutation), in the hepatitis B virus (HBV) genome basal core promoter (BCP) region is a common viral mutation in patients with chronic HBV infection. This mutation is located in the binding site of hepatocyte nuclear factor 4 (HNF4), and a number of liver‑enriched transcription factors are involved in the regulation of HBV transcription and replication. The aim of the present study was to investigate the biological characteristics of the HBV strain with this mutation, and the effect of HNF4 inhibition on the replication of this strain in vivo. The results indicated that in vivo the HBV strain with the TA mutation supported a higher level of pregenomic RNA transcription and HBV DNA replication, compared with the wild‑type strain. Furthermore, the concentration of serum HBeAg in the TA mutant group was lower than that in the wild‑type strain. Following treatment of the mice with entecavir (ETV) or tenofovir disoproxil fumarate (TDF), the transcription and replication levels of wild‑type and mutant strains were reduced. In the groups treated with TDF, the inhibition effect was more marked. In hepatocytes in which HNF4 expression was specifically inhibited, the level of 3.5 kb mRNA of HBV was reduced compared with that in mouse cells with normal HNF4 expression, and HBV DNA replication levels were also reduced to a greater extent. Furthermore, following liver‑specific knockdown of HNF4, the reduction in variant virus expression was greater than that of the wild‑type virus. In conclusion, the replication capacity of HBV with the TA mutation was increased, and the mutation was associated with a reduction in serum HBeAg levels. This mutant strain remained sensitive to ETV and TDF, and HNF4 supported a higher replication level of TA mutant HBV in vivo.
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Leng
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: En-Qiang
authors.initials: EQ
authors.lastname: Chen
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Ling-Yao
authors.initials: LY
authors.lastname: Du
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Lang
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Forensic Pathology, Medical School of Basic and Forensic Sciences, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Dao-Ying
authors.initials: DY
authors.lastname: Gong
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Forensic Pathology, Medical School of Basic and Forensic Sciences, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Fei-Jun
authors.initials: FJ
authors.lastname: Huang
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D016679:Genome, Viral; D006509:Hepatitis B / Q000097:blood / Q000276:immunology / Q000821:virology*; D006512:Hepatitis B Core Antigens / Q000276:immunology / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000276:immunology / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000097:blood / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D012367:RNA, Viral; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; C496592:HNF4A protein, human; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D051557:Hepatocyte Nuclear Factor 4; D012367:RNA, Viral