Novel robust hepatitis C virus 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 (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) 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-alpha 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.
Zhu
Qing
Q
Department of Pharmacology, Novartis Vaccines and Diagnostics, Chiron Corportion, Emeryville, CA 94608. Qing_zhu@chiron.com
Oei
Yoko
Y
Mendel
Dirk B
DB
Garrett
Evelyn N
EN
Patawaran
Montesa B
MB
Hollenbach
Paul W
PW
Aukerman
Sharon L
SL
Weiner
Amy J
AJ
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000637:transplantation; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; C479555:BILN 2061; D002219:Carbamates; D016898:Interferon-alpha; D047028:Macrocyclic Compounds; D011804:Quinolines; D013844:Thiazoles