title: Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes.
abstract: OBJECTIVE
  Little is known about the direct cytopathic effect of hepatitis B virus (HBV) and its association with particular viral genotypes or genetic mutations. We investigate HBV genotype-related differences in viral replication, antigen expression, and histopathology in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mice harboring human hepatocytes.
  
  
  METHODS
  Mice were inoculated with wild-type of different genotype strains (3 for each HBV/A2, B1, and C2) recovered from preinfected-mice sera or patient sera.
  
  
  RESULTS
  Histologic analysis of mice infected with HBV/C2 for 22-25 weeks showed abundant ground-glass appearance of the hepatocytes and fibrosis in the humanized part of the murine liver owing to the activation of hepatic stellate cells mediated by oxidative stress through transforming growth factor-beta1 signaling, whereas neither was observed with HBV/A2 and B1. The HBV-DNA level in sera was the highest in mice infected with HBV/C2 compared with those with HBV/A2 and HBV/B1 (10(9), 10(7), and 10(4) log copies/mL, respectively, P < .05) during 6-8 weeks postinoculation. HB core-related antigen excretion had a similar trend among the genotypes, whereas secretion of HB surface antigen was more pronounced for HBV/A2 followed by HBV/C2 and much less for HBV/B1. Introduction of precore stop-codon mutation in the HBV/B1 caused a significant increase in viral replication, antigen expression, and a histopathologic picture similar to HBV/C2.
  
  
  CONCLUSIONS
  By using a humanized in vivo model, we show that different HBV genotypes and even particular mutations resulted in different virologic and histopathologic outcomes of infection, indicating that particular genetic variants of HBV may be directly cytopathic in immunosuppressive conditions.
authors.affiliation: Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Fuat
authors.initials: F
authors.lastname: Kurbanov
authors.forename: Isao
authors.initials: I
authors.lastname: Maruyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
authors.forename: Isao
authors.initials: I
authors.lastname: Sakaida
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002678:Chimera / Q000378:metabolism / Q000821:virology; D003588:Cytopathogenic Effect, Viral / Q000502:physiology; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D005838:Genotype; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000503:physiopathology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D000199:Actins; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D014568:Urokinase-Type Plasminogen Activator