38 Transcomplementation of HBx protein with hydrodynamic injection restored HBV infectivity in mice. Interestingly, all revertant viruses show a restored ability to express HBx.38 By infecting chimeric mice with genotype A, B and C, differing proliferative capacity has been shown between HBV genotypes.37 In mice infected for a relatively short time, there are no morphological changes in HBV infected mice livers in Small molecule library studies.13,36 In contrast, the occurrence of liver cell damage has been reported after long-term infection of chimeric mice with HBV39 or with specific strains of HBV;40 these findings are consistent with direct cytopathic effects of HBV under certain conditions. The biological properties of a newly

identified unique strain of HBV, genotype G, which replicates only in the presence of another genotype, were confirmed using the chimeric mouse.41 Infectivity of another

novel HBV strain, identified from a Japanese patient, that is divergent from known human and ape HBV has also been confirmed.42 Titration of HBV infectivity, which previously could only be carried out using chimpanzees, can be carried out effectively using chimeric mice.43 Taking advantage of the absence of human immune cells in the chimeric mice, Noguchi et al.44 showed that hypermutation of HBV increases in human hepatocytes under interferon treatment. Dandri et al. measured viral half-life in human and chimeric mice repopulated with wooly monkey hepatocytes.45 The results clearly showed that viral half-life is shortened by immunological

mechanisms in humans with low viral levels, but not in chimeric mice where functional AG-014699 research buy immunity is absent. Hiraga et al.46 showed an absence of interference between HBV and HCV. Evaluation of therapeutic agents is the most important role for this mouse model. Tsuge et al.13 assessed the effect of interferon and lamivudine using chimeric mice. Similarly, Dandri et al.47 showed the effects of adefovir using uPA/scid mice repopulated with tupaia hepatocytes, which also support replication of human HBV. Oga et al.48 identified a novel lamivudine-resistant variant that has an amino acid substitution outside of the YMDD motif. They showed that lamivudine was ineffective against the novel mutant MCE strain. It is thus apparent that this mouse/human liver chimeric model is ideal to study the susceptibility of mutant strains to various drugs, because mutant viruses can easily be made and infected into chimeric mice.13 The model has also been utilized to evaluate viral entry inhibitors derived from the large envelope protein.49 As observed in studies on HBV, HCV infection efficiency was poor and levels of viremia were low in mice where the repopulation rate of the mouse liver with human hepatocyte was low.17,50 As shown in Figure 3, human albumin levels in mouse serum were significantly higher in mice in which measurable viremia developed (Hiraga et al. unpublished data).