Abstract
The narrow range of species permissive to infection by hepatitis C virus (HCV) presents a unique challenge to the development of useful animal models for studying HCV, as well as host immune responses and development of chronic infection and disease. Following earlier studies in chimpanzees, several unique approaches have been pursued to develop useful animal models for research while avoiding the important ethical concerns and costs inherent in research with chimpanzees. Genetically related hepatotropic viruses that infect animals are being used as surrogates for HCV in research studies; chimeras of these surrogate viruses harboring specific regions of the HCV genome are being developed to improve their utility for vaccine testing. Concurrently, genetically humanized mice are being developed and continually advanced using human factors known to be involved in virus entry and replication. Further, xenotransplantation of human hepatocytes into mice allows for the direct study of HCV infection in human liver tissue in a small animal model. The current advances in each of these approaches are discussed in the present review.
Highlights
The narrow range of species permissive to infection by hepatitis C virus (HCV) presents a unique challenge to the development of useful animal models for studying HCV, as well as host immune responses and development of chronic infection and disease
Unlike in humans where approximately 75%–85% of patients progress to chronic hepatitis, the development of chronic disease after HCV infection in chimpanzees has been recorded between 33% and >60% across studies
The conclusions which may be drawn from these studies have limitations due to the need to suppress innate antiviral defenses to establish infection, the results suggest that HCV infection could possibly be established in smaller non-human primates for future research
Summary
Over 71 million people [1] are chronically infected with hepatitis C virus (HCV), resulting in greatly increased risk of developing liver fibrosis, decompensated cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antivirals began to be accepted for use in HCV patients in the mid-2000s and as they have largely supplanted use of combined interferon-based therapies, rates of HCV virus clearance have risen steadily in treated patients [4] These drugs target the viral NS3/4 serine protease, the NS5A phosphoprotein and the NS5B RNA-dependent polymerase, inhibiting their respective functions in viral polyprotein processing and replication [5,6,7]. The need for a new animal model for early phase testing, as well as the rising incidence and prevalence of infection, highlights the need for continued research on HCV This need is compounded by the inaccessibility of the most effective treatments to those most at risk of infection, and there is an urgent call for development of prophylactics and for a deeper understanding of the replication cycle of HCV. We will discuss the progress that has been made to develop different (small) animal models with susceptibility to HCV or these closely related surrogate viruses
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