In vivo models of hepatitis B and C virus infection

Abstract

Globally, more than 500 million individuals are chronically infected with hepatitis B (HBV), delta (HDV), and/or C (HCV) viruses, which can result in severe liver disease. Mechanistic studies of viral persistence and pathogenesis have been hampered by the scarcity of animal models. The limited species and cellular host range of HBV, HDV, and HCV, which robustly infect only humans and chimpanzees, have posed challenges for creating such animal models. In this review, we will discuss the barriers to interspecies transmission and the progress that has been made in our understanding of the HBV, HDV, and HCV life cycles. Additionally, we will highlight a variety of approaches that overcome these barriers and thus facilitate in vivo studies of these hepatotropic viruses.

Keywords: hepatitis B virus; hepatitis C virus; hepatitis delta virus; mouse models; surrogate models.

Figure 1

A. Barriers to HBV species tropism. Mouse cells do not support the HBV life cycle. The expression of hNTCP renders mouse hepatocytes susceptible to HDV infection but not HBV infection. Blocks may/do occur (red question marks or dashes, respectively) at the level of nucleocapsid un-coating and also in formation/maintenance of HBV cccDNA. However, the mechanisms of HBV virion assembly and egress are functional in murine hepatocytes (green check marks). B. Barriers to HCV species tropism. Mouse cells inefficiently support the HCV life cycle. The expression of human CD81 and OCLN can facilitate the entry of viral particles into mouse cells, and HCV RNA translation is supported, whereas HCV RNA replication occurs inefficiently. Virion assembly and release can take place in mouse cells. hNTCP, human sodium taurocholate co-transporting polypeptide; rcDNA, relaxed circular DNA; cccDNA, covalently closed circular DNA; pgRNA, pre-genomic RNA; RT, reverse transcription; HSPG, heparan sulfate proteoglycan; LDLR, low density lipoprotein receptor; CLDN1, claudin 1; OCLN, occludin.

Figure 2. Xenotransplantation approaches for studying pathogenesis of hepatotropic viruses

Hepatocytes and HSCs can be isolated from human subjects. The transplantation of these cells into appropriate xenorecipient mice gives rise to human liver chimeric mice or to human hemato-lymphoid mice, respectively. Alternatively, directed differentiation approaches allow the generation of hepatocyte-like cells and HSCs from human iPS or ES cells. However, these cells engraft considerably less efficiently in commonly used xenerecipient strains. Hemato-lymphoid mice can be used to study a variety of human (lympho-) tropic viruses. Human liver chimeric mice can be used to study hepatotropic pathogens. Dually engrafted mice, which harbor both a chimeric human-mouse liver and a human immune system, can be utilized to investigate the immune response of hepatotropic viruses. HSC, hematopoietic stem cells; iPS, induced pluripotent stem cells; ES, embryonic stem cells.