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Journal of Virology, September 2001, p. 8074-8081, Vol. 75, No. 17
Department of Virology and
Immunology1 and Department of Laboratory
Animal Medicine,3 Southwest Regional Primate
Research Center, Southwest Foundation for Biomedical Research, San
Antonio, Texas 78227, and Schering-Plough Research
Institute, Kenilworth, New Jersey 070332
Received 16 March 2001/Accepted 6 June 2001
GB virus B (GBV-B) is the closest relative of hepatitis C
virus (HCV) and is an attractive surrogate model for HCV antiviral studies. GBV-B induces an acute, resolving hepatitis in tamarins. Utilizing primary cultures of tamarin hepatocytes, we have previously developed a tissue culture system that exhibits high levels of GBV-B
replication. In this report, we have extended the utility of this
system for testing antiviral compounds. Treatment with human interferon
provided only a marginal antiviral effect, while poly(I-C)
yielded >3 and 4 log units of reduction of cell-associated and
secreted viral RNA, respectively. Interestingly, treatment of
GBV-B-infected hepatocytes with ribavirin resulted in an approximately 4-log decrease in viral RNA levels. Guanosine blocked the antiviral effect of ribavirin, suggesting that inhibition of IMP dehydrogenase (IMPDH) and reduction of intracellular GTP levels were essential for
the antiviral effect. However, mycophenolic acid, another IMPDH
inhibitor, had no antiviral effect. Virions harvested from ribavirin-treated cultures exhibited a dramatically reduced specific infectivity. These data suggest that incorporation of ribavirin triphosphate induces error-prone replication with concomitant reduction
in infectivity and that reduction of GTP pools may be required for
incorporation of ribavirin triphosphate. In contrast to the in vitro
studies, no significant reduction in viremia was observed in vivo
following treatment of tamarins with ribavirin during acute infection
with GBV-B. These findings are consistent with the observation that
ribavirin monotherapy for HCV infection decreases liver disease without
a significant reduction in viremia. Our data suggest that nucleoside
analogues that induce error-prone replication could be an attractive
approach for the treatment of HCV infection if administered at
sufficient levels to result in efficient incorporation by the viral polymerase.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.17.8074-8081.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Ribavirin Induces Error-Prone Replication of GB
Virus B in Primary Tamarin Hepatocytes


*
Corresponding author. Mailing address: Department of
Virology and Immunology, Southwest Regional Primate Research Center, Southwest Foundation for Biomedical Research, 7620 N.W. Loop 410, San
Antonio, TX 78227. Phone: (210) 258-9445. Fax: (210) 670-3329. E-mail:
rlanford{at}icarus.sfbr.org.
Present address: ICN Pharmaceuticals, Costa Mesa, CA 92626.
Present address: Bayer Biological Products, Raleigh, NC 27610.
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