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Journal of Virology, February 2004, p. 2062-2071, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.2062-2071.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Development of a GB Virus B Marmoset Model and Its Validation with a Novel Series of Hepatitis C Virus NS3 Protease Inhibitors{dagger}

Helen Bright,* Anthony R. Carroll, Paul A. Watts, and Robert J. Fenton

Department of Virology, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom

Received 17 July 2003/ Accepted 28 October 2003

GB virus B (GBV-B), a flavivirus closely related to HCV, has previously been shown to infect and replicate to high titers in tamarins (Saguinus sp.). This study describes the use of GBV-B infection and replication in the common marmoset (Callithrix jacchus) for the successful development and validation of a surrogate animal model for hepatitis C virus (HCV). Infection of marmosets with GBV-B produced a viremia that peaked at 108 to 109 genome copies/ml for a period of 40 to 60 days followed by viral clearance at 60 to 80 days postinfection. Passage of the initial tamarin-derived GBV-B in marmosets produced an infectious stock that gave a more reproducible and consistent infection in the marmoset. Titration of the virus stocks in vivo indicated that they contained 1 infectious unit for every 1,000 genome copies. Cultures of primary marmoset hepatocytes were also successfully infected with GBV-B, with high levels of virus detected in supernatants and cells for up to 14 days postinfection. Treatment of GBV-B-infected hepatocyte cultures with a novel class of HCV protease inhibitor (pyrrolidine 5,5 trans-lactams) reduced viral levels by more than 2 logs. Treatment of GBV-B-infected marmosets with one such inhibitor resulted in a 3-log drop in serum viral titer over 4 days of therapy. These studies provide the first demonstration of the in vivo efficacy of a small-molecule inhibitor for HCV in an animal model and illustrate the utility of GBV-B as a surrogate animal model system for HCV.

* Corresponding author. Mailing address: Department of Virology, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Rd., Stevenage, Hertfordshire SG1 2NY, United Kingdom. Phone: 44 438 763931. Fax: 44 438 764263. E-mail: Helen.X.Bright{at}gsk.com.

{dagger} Dedicated to the memory of Paul Watts, who died suddenly.

Journal of Virology, February 2004, p. 2062-2071, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.2062-2071.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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