A novel TK-NOG based humanized mouse model for the study of HBV and HCV infections

Abstract

The immunodeficient mice transplanted with human hepatocytes are available for the study of the human hepatitis viruses. Recently, human hepatocytes were also successfully transplanted in herpes simplex virus type-1 thymidine kinase (TK)-NOG mice. In this study, we attempted to infect hepatitis virus in humanized TK-NOG mice and urokinase-type plasminogen activator-severe combined immunodeficiency (uPA-SCID) mice. TK-NOG mice were injected intraperitoneally with 6 mg/kg of ganciclovir (GCV), and transplanted with human hepatocytes. Humanized TK-NOG mice and uPA/SCID mice were injected with hepatitis B virus (HBV)- or hepatitis C virus (HCV)-positive human serum samples. Human hepatocyte repopulation index (RI) estimated from human serum albumin levels in TK-NOG mice correlated well with pre-transplantation serum ALT levels induced by ganciclovir treatment. All humanized TK-NOG and uPA-SCID mice injected with HBV infected serum developed viremia irrespective of lower replacement index. In contrast, establishment of HCV viremia was significantly more frequent in TK-NOG mice with low human hepatocyte RI (<70%) than uPA-SCID mice with similar RI. Frequency of mice spontaneously in early stage of viral infection experiment (8weeks after injection) was similar in both TK-NOG mice and uPA-SCID mice. Effects of drug treatment with entecavir or interferon were similar in both mouse models. TK-NOG mice thus useful for study of hepatitis virus virology and evaluation of anti-viral drugs.

Keywords: ALT; GCV; HBV; HCV; HSA; HSVtk; Hepatitis B virus; Hepatitis C virus; Human hepatocyte chimeric mouse; Human serum albumin; IFN; PegIFN-alpha; RI; RT-PCR; SCID; TK-NOG mouse; alanine aminotransferase; ganciclovir; hepatitis B virus; hepatitis C virus; herpes simplex virus type-1 thymidine kinase; human serum albumin; interferon; pegylated interferon-alpha; repopulation index; reverse transcript-polymerase chain reaction; severe combined immunodeficiency; uPA; uPA–SCID mouse; urokinase-type plasminogen activator.