Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection?

Masataka Tsuge

doi:10.3390/v13101920

Abstract

Chronic hepatitis B virus (HBV) infection is a global health problem that can lead to liver dysfunction, including liver cirrhosis and hepatocellular carcinoma (HCC). Current antiviral therapies can control viral replication in patients with chronic HBV infection; however, there is a risk of HCC development. HBV-related proteins may be produced in hepatocytes regardless of antiviral therapies and influence intracellular metabolism and signaling pathways, resulting in liver carcinogenesis. To understand the mechanisms of liver carcinogenesis, the effect of HBV infection in human hepatocytes should be analyzed. HBV infects human hepatocytes through transfer to the sodium taurocholate co-transporting polypeptide (NTCP). Although the NTCP is expressed on the hepatocyte surface in several animals, including mice, HBV infection is limited to human primates. Due to this species-specific liver tropism, suitable animal models for analyzing HBV replication and developing antivirals have been lacking since the discovery of the virus. Recently, a humanized mouse model carrying human hepatocytes in the liver was developed based on several immunodeficient mice; this is useful for analyzing the HBV life cycle, antiviral effects of existing/novel antivirals, and intracellular signaling pathways under HBV infection. Herein, the usefulness of human hepatocyte chimeric mouse models in the analysis of HBV-associated hepatocarcinogenesis is discussed.

Highlights

Despite the global promotion of a universal vaccination program for hepatitis B virus (HBV) infection, an estimated 257 million people still suffer from chronic HBV infection and, each year, an estimated 887,000 individuals die from HBV-related liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC) [1]
Based on a gene expression analysis using HBV-infected humanized mouse livers, the production of interleukin (IL)-8 (CXCL8) mRNA in the liver tissues was significantly upregulated by HBV infection, and CXCL8 transcriptional activation might be induced by large hepatitis B surface (HBs) proteins [88]
I have discussed the usefulness of humanized mouse models carrying human hepatocytes in the liver for analyzing HCC development

Summary

Introduction

Despite the global promotion of a universal vaccination program for hepatitis B virus (HBV) infection, an estimated 257 million people still suffer from chronic HBV infection and, each year, an estimated 887,000 individuals die from HBV-related liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC) [1]. As it is still difficult to eradicate HBV from hepatocytes with the current therapies, there is still a risk of HCC development, even when HBV replication is continuously suppressed with antiviral therapy. As humanized mice are generated from severe immunodeficient mouse lines, hepatitis does not occur in HBV-infected mice. Using this mouse model, the direct effect of HBV infection in human hepatocytes can be analyzed without host immune responses. The association between HBV infection and hepatocarcinogenesis has not been analyzed using this mouse model as its lifespan is comparatively shorter than that of normal mice, and HCC does not occur in chimeric mouse livers. I discuss the usefulness of a humanized mouse model for analyzing hepatocarcinogenesis via HBV infection

HBV Infection Is Animal Specific

Construction of a Human Hepatocyte Chimeric Mouse Model for Hepatitis

Analyzing the Association between HBV Genotype and Hepatocarcinogenesis

Analyzing HBV Integration and Hepatocarcinogenesis Using HBV-Infected

Findings

Conclusions and Future Prospects