Open AccessNovel Robust Hepatitis C Virus Mouse Efficacy Model
Author(s) -
Qing Zhu,
Yoko Oei,
Dirk B. Mendel,
Evelyn N. Garrett,
Montesa Patawaran,
Paul W. Hollenbach,
Sharon L. Aukerman,
Amy J. Weiner
Publication year - 2006
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00413-06
Subject(s) - replicon , hepatitis c virus , in vivo , virology , viral replication , protease inhibitor (pharmacology) , ns3 , hepacivirus , biology , interferon , hepatitis c , ribavirin , protease , drug discovery , virus , viral load , bioinformatics , dna , enzyme , biochemistry , microbiology and biotechnology , antiretroviral therapy , plasmid
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-α) 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-α 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.