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Journal of Virology, February 2008, p. 1665-1678, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02113-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of Three Interferon-Inducible Cellular Enzymes That Inhibit the Replication of Hepatitis C Virus

Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine,¹ Institute for Hepatitis Virus Research, Hepatitis B Foundation, 3805 Old Easton Road, Doylestown, Pennsylvania 18902,² Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111³

Received 24 September 2007/ Accepted 30 November 2007

Hepatitis C virus (HCV) infection is a common cause of chronic hepatitis and is currently treated with alpha interferon (IFN-)-based therapies. However, the underlying mechanism of IFN- therapy remains to be elucidated. To identify the cellular proteins that mediate the antiviral effects of IFN-, we created a HEK293-based cell culture system to inducibly express individual interferon-stimulated genes (ISGs) and determined their antiviral effects against HCV. By screening 29 ISGs that are induced in Huh7 cells by IFN- and/or up-regulated in HCV-infected livers, we discovered that viperin, ISG20, and double-stranded RNA-dependent protein kinase (PKR) noncytolytically inhibited the replication of HCV replicons. Mechanistically, inhibition of HCV replication by ISG20 and PKR depends on their 3'-5' exonuclease and protein kinase activities, respectively. Moreover, our work, for the first time, provides strong evidence suggesting that viperin is a putative radical S-adenosyl-L-methionine (SAM) enzyme. In addition to demonstrating that the antiviral activity of viperin depends on its radical SAM domain, which contains conserved motifs to coordinate [4Fe-4S] cluster and cofactor SAM and is essential for its enzymatic activity, mutagenesis studies also revealed that viperin requires an aromatic amino acid residue at its C terminus for proper antiviral function. Furthermore, although the N-terminal 70 amino acid residues of viperin are not absolutely required, deletion of this region significantly compromises its antiviral activity against HCV. Our findings suggest that viperin represents a novel antiviral pathway that works together with other antiviral proteins, such as ISG20 and PKR, to mediate the IFN response against HCV infection.

Published ahead of print on 12 December 2007.

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