Table 6.

Marmoset and alternative animal models of hepatitis C virus (HCV) infection.

Marmoset model of hepatitis C virus infection
Advantages	Disadvantages	Reference
Cheaper and easier to breed in captivity Susceptible to GBV-B Infection rate and severity of acute infection similar to that in humans Acute viremia similar to that in chimpanzee Chronic, progressive disease similar to human HCV Acute disease exacerbation associated with chronic hepatitis Persistent infection established using HCV chimera Production of interferon-γ coincides with reduction of viral load Virus-specific T cells found predominately in the liver	Not susceptible to infection with HCV; studies rely on use of monkey-tropic viruses Infection may be acute or chronic depending on host Little characterization of immune response to infection, particularly between acute and chronic infection Humoral response to HCV infection requires further investigation Existence of mechanisms of T cell memory require further investigation	(Lanford et al., 2003; Bright et al., 2004; Jacob et al., 2004; Woollard et al., 2008; Weatherford et al., 2009; Iwasaki et al., 2011; Manickam et al., 2016)

Alternative animal models of hepatitis C virus infection
Model	Advantages	Disadvantages	Reference
Chimpanzee	First animal model for HCV infection Best characterized model of HCV infection In vivo virus replication Viremia Development of anti-HCV antibodies Elevated serum liver enzymes and necro-inflammatory changes in liver 60% of animals develop chronic disease	Natural course of infection different from that in humans Low availability of animals High costs Ethical concerns Disease course is significantly attenuated compared with human disease Limited availability of immunological reagents and tools	(Alter et al., 1978; Fernandez et al., 2004; Folgori et al., 2006; Puig et al., 2006; Bukh et al., 2008; Houghton, 2009; Manickam and Reeves, 2014; Pfaender et al., 2014)
Tamarins	Surrogate model of HCV infection Susceptible to experimental infection with GBV-B Persistent viremia Appearance of antiviral antibodies Induction of hepatitis Produces HCV-like disease Study of immune response associated with acute viral clearance	Surrogate model of HCV infection Disease is typically acute and self-resolving Failure to establish long-term or chronic viral persistence Not useful for vaccine development Difficult and costly to breed Limited availability of immunological reagents and tools	(Deinhardt et al., 1967; Beames et al., 2000; Beames et al., 2001; Lanford et al., 2003; Martin et al., 2003; Nam et al., 2004; Ishii et al., 2007; Takikawa et al., 2010; Iwasaki et al., 2011; Dale et al., 2020)
Tree Shrew	Susceptible to infection with HCV Persistent liver infection with some histological indications of liver disease Used in metabolomics studies to identify biomarkers of HCV infection Intermittent viremia and serum antibodies	Transient, self-resolving infection Intermittent viremia only if immunosuppressed Limited viral replication Limited availability of immunological reagents and tools	(Xie et al., 1998; Amako et al., 2010; Sun et al., 2013; Manickam and Reeves, 2014; Feng et al., 2017)
Mice	Can be manipulated to transgenically express individual or combinations of HCV gene products Transgenic mice useful for study of intrahepatic adaptive immune response Lots of well characterized strains, each with their own pros and cons Useful for antiviral drug evaluation Useful for immunization and challenge studies	Naturally resistant to HCV infection Disease severity is strain-specific Caveats associated with use of transgenic animals, e.g., failure to establish inflammatory milieu that is established during infection Chimeric mice are immunodeficient and thus are not useful for studies of HCV pathogenesis Lack of progressive liver pathology	(Galun et al., 1995; Mercer et al., 2001; Meuleman et al., 2005; Flint et al., 2006; Yang et al., 2008; Ploss et al., 2009; Bissig et al., 2010; Bitzegeio et al., 2010; Washburn et al., 2011; Anggakusuma et al., 2014; Hartlage et al., 2019)