Hepatitis C virus replication in mice with chimeric human livers

Lack of a small animal model of the human hepatitis C virus (HCV) has imped ed development of antiviral therapies against this epidemic infection. By t ransplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (Alb-uPA), we generated mice with chimeric human liver s. Homozygosity of Alb-uPA was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV inf ections with high viral titers after inoculation with infected human serum. Initial increases in total viral load were up to 1950-fold, with replicati on confirmed by detection of negative-strand viral RNA in transplanted live rs. HCV viral proteins were localized to human hepatocyte nodules, and infe ction was serially passaged through three generations of mice confirming bo th synthesis and release of infectious viral particles. These chimeric mice represent the first murine model suitable for studying the human hepatitis C virus in vivo.