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Background and Aim The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV‐specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV‐TK‐NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV‐TK) mice in which the host immune system was not impaired. Methods Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV‐treated mice were transplanted with 1 × 106 hepatocytes from HBV‐transgenic (HBV‐Tg) mice. Results Serum alanine aminotransferase levels in HSV‐TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV‐Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)‐positive areas in the liver tissue were observed for at least 20 weeks after HBsAg‐positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV‐Tg hepatocyte‐replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV‐TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon‐γ‐producing cells were increased in non‐replaced mice. Conclusions A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV‐infected patients and can be used to develop a new strategy to treat chronic HBV infection.

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