The usefulness of a newly developed HCV assay,51 and infectivity of a newly identified intergenotypic recombinant strain,52 have been reported using the chimeric mice. Using the remarkable replication ability of the JFH1 genotype 2a strain,53 infectivity of JFH1 or intergenotypic chimeric viral particles, previously shown in cell culture, has now been shown to be infectious in chimeric mice.54–56 Infectivity of viruses that were replicated in chimeric mice in cell culture has also been shown, and virus fitness has been studied.55,56 The role

of the HCV core+1 open reading frame and core cis-acting RNA elements has also been examined using the chimeric Raf inhibitor virus.57 These elegant studies have the limitation that the non-structural part of the virus is limited to that of JFH1. Hiraga et al.14 have shown that infectious clones of genotype 1a and JFH1 can be infected with direct injection of in vitro transcribed RNA into the mouse liver.14 Similarly, Kimura et al.15 reported check details the establishment of infectious clones of genotype 1b and ablation of RNA polymerase by site-directed mutagenesis abolish infectivity. These infectious clones will be useful for the study of drug-resistant strains. The model of HCV infection

has also been used to show that infection of the virus can be prevented by antibodies against CD81,58 polyclonal human immunoglobulin directed to a similar strain,59 and amphipathic DNA polymers.60 Notably, the presence of broadly neutralizing antibodies to HCV that protect against heterologous viral infection has been reported, suggesting the possibility of a prophylactic vaccine against HCV.61 With respect to evasion of the virus against the innate immune response,

altered intrahepatic expression profiles in the early phase of infection is of particular interest. The chimeric mice model is ideal for such studies; cross-hybridization of mouse and human can be avoided by careful experimental procedures.62 Microarray analysis of livers of HCV infected and non-infected 上海皓元 mice showed transcriptional activation of genes related to innate immune response, lipid metabolism, endoplasmic reticulum (ER) stress and apoptosis in HCV-infected mice.63,64 The HCV infected mouse model is particularly useful for the study of newly developed HCV agents. The effect of recently developed chemicals and a unique therapy using intrahepatic lymphocytes have been shown using this model (Table 1). However, none of these therapies have yet been able to completely eradicate HCV from mice. It is noteworthy that ultra-rapid cardiotoxicity has been reported with the protease inhibitor BILN 2061 in the uPA/scid mice, but not in scid mice, implicating involvement of the uPA transgene.72 Care should therefore be taken in interpreting the results obtained by this model. Development of a small animal model using human hepatocyte chimeric mice has enabled us to study key aspects of HBV and HCV biology.