Novel Robust Hepatitis C Virus Mouse Efficacy Model
Qing Zhu,1* Yoko Oei,1 Dirk B. Mendel,1 Evelyn N. Garrett,2 Montesa B. Patawaran,1 Paul W. Hollenbach,3 Sharon L. Aukerman,1, and Amy J. Weiner4,
Departments of Pharmacology,1 Experimental Pathology,2 Translational Medicine,3 Vaccines, Chiron Corporation, 4560 Horton Street, Emeryville, California 946084
Received 3 April 2006/ Returned for modification 7 June 2006/ Accepted 18 July 2006
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 (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN- combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.
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