Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes.
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.
Sugiyama
Masaya
M
Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Tanaka
Yasuhito
Y
Kurbanov
Fuat
F
Maruyama
Isao
I
Shimada
Takashi
T
Takahashi
Satoru
S
Shirai
Tomoyuki
T
Hino
Keisuke
K
Sakaida
Isao
I
Mizokami
Masashi
M
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
D000199:Actins; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D014568:Urokinase-Type Plasminogen Activator