Towards a small animal model for hepatitis C

Abstract

Hepatitis C virus (HCV) causes chronic liver disease and affects an estimated 3% of the world's population. Options for the prevention or therapy of HCV infection are limited; there is no vaccine and the nonspecific, interferon-based treatments now in use are frequently ineffective and have significant side effects. A small-animal model for HCV infection would significantly expedite antiviral compound development and preclinical testing, as well as open new avenues to decipher the mechanisms that underlie viral pathogenesis. The natural species tropism of HCV is, however, limited to humans and chimpanzees. Here, we discuss the prospects of developing a mouse model for HCV infection, taking into consideration recent results on HCV entry and replication, and new prospects in xenotransplantation biology. We highlight three independent, but possibly complementary, approaches towards overcoming current species barriers and generating a small-animal model for HCV pathogenesis.

Figure 1

Strategies to create mouse models for HCV. Strategy I, viral adaptation; Strategy II, genetic host humanization; Strategy III, humanization by xenotransplantation. Refer to text for further details. HCV, hepatitis C virus.

Figure 2

Blocks in HCV species tropism. Mouse cells inefficiently support the HCV life cycle. The expression of human CD81 and OCLN can overcome the block in entry, and HCV RNA translation is supported, whereas HCV RNA replication can only occur under selective pressure. Whether the late stages of the HCV life cycle (virion assembly and release) can take place in mouse cells is unclear. CD, cluster of differentiation; CLDN1, claudin 1; GAG, glycosaminoglycan; HCV, hepatitis C virus; LDLR, low density lipoprotein receptor; OCLN, occludin.