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The majority of HCV infection develops chronic infection,which causes steatosis,cirrhosis and hepatocellular carcinoma.However,understanding HCV chronicity and pathogenesis is hampered by its narrow host range.Chimpanzees are by far the best available animal model of HCV infection,but they are not a good host to study chronic hepatitis and associated HCC.Several sophisticated approaches,represented by uPA-SCID and Fah-/-Rag2-/-IL2rg-/-model,to engraft primary human liver cells or liver progenitor cells to immunodeficient mice have revealed how HCV infects and replicates in vivo.These models,however,are limited by lack of adaptive immune system and liver pathology,among other technical hurdles associated with the transplants.Two additional humanized mouse models have developed.AFC8-huHSC/hep model engrafts both human hematopoietic stem cells and hepatocyte progenitor cells to partially reconstitute human innate system,where HCV genome in liver,virus specific T cell response in periphery and hepatic fibrosis can be detected.Rosa26-Fluc model ectopically expresses human receptor CD81 and Occludin(OCLN)carried by an adenovirus vector,thus enables HCV entry and transient replication in mouse liver cells in an immune competent background.Recently,we generated transgenic mice harboring both human CD81 and occludin genes(C/O Tg)are permissive to HCV infection at a chronicity rate comparable to humans.HCV natural infection with complete viral replication cycle and hepatopathologic manifestations is recapitulated in an immune competent host.