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Antimicrobial Agents and Chemotherapy, October 2006, p. 3260-3268, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00413-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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. Weiner^4,

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.

S.L.A. and A.J.W. contributed equally to this work.

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