title: Adeno-Associated Virus Vector Mediated Delivery of the HBV Genome Induces Chronic Hepatitis B Virus Infection and Liver Fibrosis in Mice.
abstract: Liver cirrhosis and hepatocellular carcinomas are major health problems of chronic hepatitis B virus (HBV) infection. To date, rare model has reproduced liver fibrosis associated with long-term HBV infection which in turn has hindered both the understanding of HBV biology and the development of new treatment options. Here, using adeno-associated virus serotype 8 (AAV8) mediated delivery of a 1.2-kb HBV genome, we successfully generated a chronic HBV infectious mouse model that presents the associated liver fibrosis observed following human infection. After AAV8/HBV1.2 vector administration, mice demonstrated effective HBV replication and transcription which resulted in HBV antigen expression and viremia over 6 months. Although no obvious acute inflammatory response was noted, these mice still developed chronic liver disease and hepatic fibrogenesis as demonstrated by increased ground glass-like hepatocytes, an increasing trend of collagen deposition and upregulated fibrosis markers, including type I collagen, type III collagen, tissue inhibitor of metalloproteinase (TIMP), and transforming growth factor-β1(TGF-β1). Taken together, AAV-mediated HBV gene delivery to the mouse liver, induced HBV persistent infection accompanied by liver fibrosis which can serve as a model for investigating the precise mechanisms underlying liver fibrosis following chronic HBV infection as well as for the potential development of novel therapeutics.
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.affiliation: Key Laboratory of Immunity and Infection, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Haisheng
authors.initials: H
authors.lastname: Yu
authors.affiliation: Gene Therapy Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Li
authors.affiliation: Gene Therapy Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hirsch
authors.affiliation: Key Laboratory of Immunity and Infection, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Gene Therapy Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China; MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Wuping
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000008:administration & dosage*; D016679:Genome, Viral; D057809:HEK293 Cells; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000821:virology*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000821:virology*; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014766:Viremia / Q000235:genetics / Q000821:virology*; D014779:Virus Replication
chemical_list: D012333:RNA, Messenger