This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jiang, D.
Right arrow Articles by Guo, J.-T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiang, D.
Right arrow Articles by Guo, J.-T.

 Previous Article  |  Next Article 

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{triangledown}

Dong Jiang,1 Haitao Guo,1 Chunxiao Xu,3 Jinhong Chang,1,3 Baohua Gu,1 Lijuan Wang,1 Timothy M. Block,1,2 and Ju-Tao Guo1*

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-{alpha})-based therapies. However, the underlying mechanism of IFN-{alpha} therapy remains to be elucidated. To identify the cellular proteins that mediate the antiviral effects of IFN-{alpha}, 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-{alpha} 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.

* Corresponding author. Mailing address: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902. Phone: (215) 489-4929. Fax: (215) 489-4920. E-mail: jg362{at}drexel.edu

{triangledown} Published ahead of print on 12 December 2007.

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.



This article has been cited by other articles:

  • Chua, P. K., McCown, M. F., Rajyaguru, S., Kular, S., Varma, R., Symons, J., Chiu, S. S., Cammack, N., Najera, I. (2009). Modulation of alpha interferon anti-hepatitis C virus activity by ISG15. J. Gen. Virol. 90: 2929-2939 [Abstract] [Full Text]  
  • Wang, N., Liang, Y., Devaraj, S., Wang, J., Lemon, S. M., Li, K. (2009). Toll-Like Receptor 3 Mediates Establishment of an Antiviral State against Hepatitis C Virus in Hepatoma Cells. J. Virol. 83: 9824-9834 [Abstract] [Full Text]  
  • Qiu, L.-Q., Cresswell, P., Chin, K.-C. (2009). Viperin is required for optimal Th2 responses and T-cell receptor-mediated activation of NF-{kappa}B and AP-1. Blood 113: 3520-3529 [Abstract] [Full Text]  
  • Hinson, E. R., Cresswell, P. (2009). The N-terminal Amphipathic {alpha}-Helix of Viperin Mediates Localization to the Cytosolic Face of the Endoplasmic Reticulum and Inhibits Protein Secretion. J. Biol. Chem. 284: 4705-4712 [Abstract] [Full Text]  
  • Guo, H., Jiang, D., Ma, D., Chang, J., Dougherty, A. M., Cuconati, A., Block, T. M., Guo, J.-T. (2009). Activation of Pattern Recognition Receptor-Mediated Innate Immunity Inhibits the Replication of Hepatitis B Virus in Human Hepatocyte-Derived Cells. J. Virol. 83: 847-858 [Abstract] [Full Text]  
  • Chan, Y.-L., Chang, T.-H., Liao, C.-L., Lin, Y.-L. (2008). The Cellular Antiviral Protein Viperin Is Attenuated by Proteasome-Mediated Protein Degradation in Japanese Encephalitis Virus-Infected Cells. J. Virol. 82: 10455-10464 [Abstract] [Full Text]  
  • Proud, D., Turner, R. B., Winther, B., Wiehler, S., Tiesman, J. P., Reichling, T. D., Juhlin, K. D., Fulmer, A. W., Ho, B. Y., Walanski, A. A., Poore, C. L., Mizoguchi, H., Jump, L., Moore, M. L., Zukowski, C. K., Clymer, J. W. (2008). Gene Expression Profiles during In Vivo Human Rhinovirus Infection: Insights into the Host Response. Am. J. Respir. Crit. Care Med. 178: 962-968 [Abstract] [Full Text]  
  • Pagliaccetti, N. E., Eduardo, R., Kleinstein, S. H., Mu, X. J., Bandi, P., Robek, M. D. (2008). Interleukin-29 Functions Cooperatively with Interferon to Induce Antiviral Gene Expression and Inhibit Hepatitis C Virus Replication. J. Biol. Chem. 283: 30079-30089 [Abstract] [Full Text]  
  • Wright, H. J., Matthews, J. B., Chapple, I. L. C., Ling-Mountford, N., Cooper, P. R. (2008). Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils. J. Immunol. 181: 5775-5784 [Abstract] [Full Text]  
  • Chang, J., Guo, J.-T., Jiang, D., Guo, H., Taylor, J. M., Block, T. M. (2008). Liver-Specific MicroRNA miR-122 Enhances the Replication of Hepatitis C Virus in Nonhepatic Cells. J. Virol. 82: 8215-8223 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»