Hepatitis C virus (HCV) is an important and underreported infectious disease, causing chronic infection in ∼71 million people worldwide. The limited host range of HCV, which robustly infects only humans and chimpanzees, has made studying this virus in vivo challenging and hampered the development of a desperately needed vaccine. The restrictions and ethical concerns surrounding biomedical research in chimpanzees has made the search for an animal model all the more important. In this review, we discuss different approaches that are being pursued toward creating small animal models for HCV infection. Although efforts to use a nonhuman primate species besides chimpanzees have proven challenging, important advances have been achieved in a variety of humanized mouse models. However, such models still fall short of the overarching goal to have an immunocompetent, inheritably susceptible in vivo platform in which the immunopathology of HCV could be studied and putative vaccines development. Alternatives to overcome this include virus adaptation, such as murine-tropic HCV strains, or the use of related hepaciviruses, of which many have been recently identified. Of the latter, the rodent/rat hepacivirus from Rattus norvegicus species-1 (RHV-rn1) holds promise as a surrogate virus in fully immunocompetent rats that can inform our understanding of the interaction between the immune response and viral outcomes (i.e., clearance vs. persistence). However, further characterization of these animal models is necessary before their use for gaining new insights into the immunopathogenesis of HCV and for conceptualizing HCV vaccines.
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