A hepatitis C virus xenograft mouse efficacy model.
The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive, whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line. The model has been validated by demonstrating that both a small molecule NS3/4A protease inhibitor (BILN 2061) and human interferon- alpha (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. The efficacy of protease inhibitor plus IFN-alpha demonstrated the application of the model for testing compounds in combination therapies. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo.
Zhu
Qing
Q
HCV Vaccine Research, Novartis Vaccines and Diagnostics, Emeryville, CA, USA.
Weiner
Amy J
AJ
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D016513:Mice, SCID; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014183:Transplantation, Heterologous
D012367:RNA, Viral