Murine models of hepatitis C: What can we look forward to?

Abstract

The study of interactions between hepatitis C virus (HCV) with its mammalian host, along with the development of more effective therapeutics and vaccines has been delayed by the lack of a suitable small animal model. HCV readily infects only humans and chimpanzees, which poses logistic, economic and ethical challenges with analyzing HCV infection in vivo. Progress has been made in understanding the determinants that dictate HCV’s narrow host range providing a blueprint for constructing a mouse model with inheritable susceptibility to HCV infection. Indeed, genetically humanized mice were generated that support viral uptake, replication and production of infectious virions – albeit at low levels. These efforts are complemented with attempts to select for viral variants that are inherently more capable of replicating in non-human species. In parallel, engraftment of relevant human tissues into improved xenorecipients is being continuously refined. Incorporating advances in stem-cell-biology and tissue engineering may allow the generation of patient-specific humanized mice. Construction of such mouse “avatars” may allow analyzing functionally patient-specific differences with respect to susceptibility to infection, disease progression and responses to treatment. In this review, we discuss the three, before mentioned approaches to overcome current species barriers and generate a small animal model for HCV infection, i.e. genetic modification of mice to increase their susceptibility to the virus; genetic modification of HCV, to increase its pathogenicity for mice; and the introduction of human liver and immune cells into immunodeficient mice, to create “humanized” mice. Although in the foreseeable future there will not be a single model that perfectly mimics the natural course of HCV in humans there is reason for optimism. The spectrum of murine animal models for hepatitis C provides a broad arsenal for analyzing the disease. These models may play an important role by prioritizing vaccine candidates and possibly refining combination anti-viral drug therapies. This article forms part of a symposium in Anti-viral Research on “Hepatitis C: next steps toward global eradication.”

The Strange, Expanding World of Animal Hepaciviruses

“…Development of a new tractable animal model therefore remains a top priority for HCV researchers (27, 30, 52, 65, 75, 87–96). Over the years, several models of immunodeficient mice engrafted with human liver cells have been developed (95, 97, 98). Recently, mice engineered to express human versions of the HCV entry factors were reported to sustain HCV replication when crossed to innate immune– deficient strains (STAT1, IRF, IRF7) (95, 99).…”

Surveying the global virome: Identification and characterization of HCV-related animal hepaciviruses

“…More recently, mice engineered to express human versions of the HCV entry factors were described. These permitted the entire HCV lifecycle when crossed to innate immune deficient strains, such as STAT1, IRF1 and IRF7 knock-outs (Dorner et al, 2013; von Schaewen and Ploss, 2014). Drawbacks of this model include low levels of replication and an increasing need to blunt innate immune pathways to achieve more efficient replication.…”

Expanding the Host Range of Hepatitis C Virus through Viral Adaptation

“…While humans and chimpanzees are readily susceptible to HCV infection, most other species—with the exception of intermittent, sporadic viremia in tree shrews—appear to be resistant (reviewed in reference 1). Resistance of mice to HCV is multifactorial and determined at least by blocks in viral entry and replication (reviewed in reference 2).…”

“…The differential abilities of mouse and human CD81 and OCLN to support viral entry have been mapped to amino acids in their second extracellular loops (11, 18). While infectious HCV particles can assemble in mouse liver cells in vitro (19) and in vivo (17), HCV RNA replication in mice is limited, presumably by a combination of innate antiviral immune responses (17, 20–23) and possibly by poor compatibility between murine orthologues of replication cofactors and the virally encoded components of the HCV replication machinery (1). …”