Development of a GB virus B marmoset model and its validation with a novel series of hepatitis C virus NS3 protease inhibitors.
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 10(8) to 10(9) 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.
Bright
Helen
H
Department of Virology, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom. Helen.X.Bright@gsk.com
Carroll
Anthony R
AR
Watts
Paul A
PA
Fenton
Robert J
RJ
D000818:Animals; D002144:Callithrix / Q000821:virology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018178:Flaviviridae Infections / Q000188:drug therapy / Q000503:physiopathology / Q000662:veterinary* / Q000821:virology; D029406:GB virus B / Q000187:drug effects / Q000472:pathogenicity*; D006526:Hepatitis C / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy / Q000503:physiopathology* / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012452:Saguinus / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases