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Journal of Virology, October 2003, p. 10769-10779, Vol. 77, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.20.10769-10779.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cytopathic and Noncytopathic Interferon Responses in Cells Expressing Hepatitis C Virus Subgenomic Replicons

Ju-Tao Guo, Qing Zhu, and Christoph Seeger*

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

Received 25 April 2003/ Accepted 22 July 2003

Hepatitis C virus (HCV) is the only known positive-stranded RNA virus that causes persistent lifelong infections in humans. Accumulation of HCV RNA can be inhibited with alpha interferon (IFN-{alpha}) in vivo and in culture cells. We used cell-based assay systems to investigate the mechanisms responsible for the cytokine-induced inhibition of HCV replication. The results showed that IFN-{alpha} could suppress the accumulation of viral RNA by a noncytopathic pathway and could also induce apoptosis of virally infected cells in a concentration- and cell line-dependent fashion. Whereas the noncytopathic IFN-{alpha} response depended on a functional Jak-STAT signal transduction pathway, it did not appear to require double-stranded RNA-dependent pathways. Moreover, we found that functional proteasomes were required for establishment of the IFN-{alpha} response against HCV. Based on the results described in this study we propose a model for the mechanism by which IFN-{alpha} therapy suppresses HCV replication in chronic infections by both cytopathic and noncytopathic means.

* 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, October 2003, p. 10769-10779, Vol. 77, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.20.10769-10779.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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