Direct Cytopathic Effects of Particular Hepatitis B Virus Genotypes in Severe Combined Immunodeficiency Transgenic With Urokinase-Type Plasminogen Activator Mouse With Human Hepatocytes

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Gastroenterology. 2008 Oct 29. [Epub ahead of print]

Direct Cytopathic Effects of Particular Hepatitis B Virus Genotypes in Severe

Combined Immunodeficiency Transgenic With Urokinase-Type Plasminogen Activator

Mouse With Human Hepatocytes.

Sugiyama M, Tanaka Y, Kurbanov F, Maruyama I, Shimada T, Takahashi S, Shirai T,

Hino K, Sakaida I, Mizokami M.

Department of Clinical Molecular Informative Medicine, , Nagoya City University

Graduate School of Medical Sciences, Nagoya, Japan.

BACKGROUND & AIMS: 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.

PMID: 19041311 [PubMed - as supplied by publisher]