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J Virol, July 1998, p. 5638-5647, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Small Yeast RNA Blocks Hepatitis C Virus Internal Ribosome Entry Site (HCV IRES)-Mediated Translation and Inhibits Replication of a Chimeric Poliovirus under Translational Control of the HCV IRES Element

Saumitra Das,1 Michael Ott,2 Akemi Yamane,1 Weimin Tsai,1 Matthias Gromeier,3 Frederick Lahser,3 Sanjeev Gupta,2 and Asim Dasgupta1,*

Department of Microbiology and Immunology and Jonsson Comprehensive Cancer Center, School of Medicine, University of California, Los Angeles, California 900951; Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461-16022; and Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794-52223

Received 5 December 1997/Accepted 30 March 1998

Hepatitis C virus (HCV) infection frequently leads to chronic hepatitis and cirrhosis of the liver and has been linked to development of hepatocellular carcinoma. We previously identified a small yeast RNA (IRNA) capable of specifically inhibiting poliovirus (PV) internal ribosome entry site (IRES)-mediated translation. Here we report that IRNA specifically inhibits HCV IRES-mediated translation both in vivo and in vitro. A number of human hepatoma (Huh-7) cell lines expressing IRNA were prepared and characterized. Constitutive expression of IRNA was not detrimental to cell growth. HCV IRES-mediated cap-independent translation was markedly inhibited in cells constitutively expressing IRNA compared to control hepatoma cells. However, cap-dependent translation was not significantly affected in these cell lines. Additionally, Huh-7 cells constitutively expressing IRNA became refractory to infection by a PV-HCV chimera in which the PV IRES is replaced by the HCV IRES. In contrast, replication of a PV-encephalomyocarditis virus (EMCV) chimera containing the EMCV IRES element was not affected significantly in the IRNA-producing cell line. Finally, the binding of the La autoantigen to the HCV IRES element was specifically and efficiently competed by IRNA. These results provide a basis for development of novel drugs effective against HCV infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Jonsson Comprehensive Cancer Center, University of California, 10833 Le Conte Ave., Los Angeles, CA 90095-1747. Phone: (310) 206-8649. Fax: (310) 206-3865. E-mail: dasgupta{at}ucla.edu.

J Virol, July 1998, p. 5638-5647, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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