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Journal of Virology, September 2001, p. 8516-8523, Vol. 75, No. 18
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.18.8516-8523.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Effect of Alpha Interferon on the Hepatitis C
Virus Replicon
Ju-Tao
Guo,1
Vadim V.
Bichko,2 and
Christoph
Seeger1,*
Institute for Cancer Research, Fox Chase
Cancer Center, Philadelphia, Pennsylvania
19111,1 and Anadys Pharmaceuticals, San Diego,
California 921212
Received 13 March 2001/Accepted 12 June 2001
Chronic hepatitis C virus (HCV) infections can be cured only in a
fraction of patients treated with alpha interferon (IFN-
) and
ribavirin combination therapy. The mechanism of the IFN-
response
against HCV is not understood, but evidence for a role for viral
nonstructural protein 5A (NS5A) in IFN resistance has been provided. To
elucidate the mechanism by which NS5A and possibly other viral proteins
inhibit the cellular antiviral program, we have constructed a
subgenomic replicon from a known infectious HCV clone and demonstrated
that it has an approximately 1,000-fold-higher transduction efficiency
than previously used subgenomes. We found that IFN-
reduced
replication of HCV subgenomic replicons approximately 10-fold. The
estimated half-life of viral RNA in the presence of the cytokine was
about 12 h. HCV replication was sensitive to IFN-
independently
of whether the replicon expressed an NS5A protein associated with
sensitivity or resistance to the cytokine. Furthermore, our results
indicated that HCV replicons can persist in Huh7 cells in the presence
of high concentrations of IFN-
. Finally, under our conditions,
selection for IFN-
-resistant variants did not occur.
*
Corresponding author. Mailing address: Institute for
Cancer Research, Fox Chase Cancer Center, 7701 Burholme Ave.,
Philadelphia, PA 19111. Phone: (215) 718-4312. Fax: (215) 728-4329. E-mail: c_seeger{at}fccc.edu.
Journal of Virology, September 2001, p. 8516-8523, Vol. 75, No. 18
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.18.8516-8523.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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