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 Gale, M.
Right arrow Articles by Katze, M. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gale, M., Jr.
Right arrow Articles by Katze, M. G.

 Previous Article  |  Next Article 

Journal of Virology, August 1999, p. 6506-6516, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Antiapoptotic and Oncogenic Potentials of Hepatitis C Virus Are Linked to Interferon Resistance by Viral Repression of the PKR Protein Kinase

Michael Gale Jr.,1,* Bart Kwieciszewski,2 Michelle Dossett,1 Haruhisa Nakao,2 and Michael G. Katze1,2

Department of Microbiology, School of Medicine,1 and Regional Primate Research Center,2 University of Washington, Seattle, Washington 98195

Received 19 February 1999/Accepted 3 May 1999

Hepatitis C virus (HCV) is prevalent worldwide and has become a major cause of liver dysfunction and hepatocellular carcinoma. The high prevalence of HCV reflects the persistent nature of infection and the large frequency of cases that resist the current interferon (IFN)-based anti-HCV therapeutic regimens. HCV resistance to IFN has been attributed, in part, to the function of the viral nonstructural 5A (NS5A) protein. NS5A from IFN-resistant strains of HCV can repress the PKR protein kinase, a mediator of the IFN-induced antiviral and apoptotic responses of the host cell and a tumor suppressor. Here we examined the relationship between HCV persistence and resistance to IFN therapy. When expressed in mammalian cells, NS5A from IFN-resistant HCV conferred IFN resistance to vesicular stomatitis virus (VSV), which normally is sensitive to the antiviral actions of IFN. NS5A blocked viral double-stranded RNA (dsRNA)-induced PKR activation and phosphorylation of eIF-2alpha in IFN-treated cells, resulting in high levels of VSV mRNA translation. Mutations within the PKR-binding domain of NS5A restored PKR function and the IFN-induced block to viral mRNA translation. The effects due to NS5A inhibition of PKR were not limited to the rescue of viral mRNA translation but also included a block in PKR-dependent host signaling pathways. Cells expressing NS5A exhibited defective PKR signaling and were refractory to apoptosis induced by exogenous dsRNA. Resistance to apoptosis was attributed to an NS5A-mediated block in eIF-2alpha phosphorylation. Moreover, cells expressing NS5A exhibited a transformed phenotype and formed solid tumors in vivo. Disruption of apoptosis and tumorogenesis required the PKR-binding function of NS5A, demonstrating that these properties may be linked to the IFN-resistant phenotype of HCV.

* Corresponding author. Present address: Department of Microbiology and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., NA6.300, Dallas, TX 75235-9048. Phone: (214) 648-5940. Fax: (214) 648-5905. E-mail: mgale{at}mednet.swmed.edu.

Journal of Virology, August 1999, p. 6506-6516, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Masaki, T., Suzuki, R., Murakami, K., Aizaki, H., Ishii, K., Murayama, A., Date, T., Matsuura, Y., Miyamura, T., Wakita, T., Suzuki, T. (2008). Interaction of Hepatitis C Virus Nonstructural Protein 5A with Core Protein Is Critical for the Production of Infectious Virus Particles. J. Virol. 82: 7964-7976 [Abstract] [Full Text]  
  • Munoz de Rueda, P., Casado, J., Paton, R., Quintero, D., Palacios, A., Gila, A., Quiles, R., Leon, J., Ruiz-Extremera, A., Salmeron, J. (2008). Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of Hepatitis C Virus Genotype 1 and Their Relationships to Pegylated Interferon-Ribavirin Treatment Responses. J. Virol. 82: 6644-6653 [Abstract] [Full Text]  
  • Garcia, M. A., Gil, J., Ventoso, I., Guerra, S., Domingo, E., Rivas, C., Esteban, M. (2006). Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action. Microbiol. Mol. Biol. Rev. 70: 1032-1060 [Abstract] [Full Text]  
  • Xiang, J., McLinden, J. H., Chang, Q., Kaufman, T. M., Stapleton, J. T. (2006). An 85-aa segment of the GB virus type C NS5A phosphoprotein inhibits HIV-1 replication in CD4+ Jurkat T cells. Proc. Natl. Acad. Sci. USA 103: 15570-15575 [Abstract] [Full Text]  
  • Samuel, M. A., Whitby, K., Keller, B. C., Marri, A., Barchet, W., Williams, B. R. G., Silverman, R. H., Gale, M. Jr., Diamond, M. S. (2006). PKR and RNase L Contribute to Protection against Lethal West Nile Virus Infection by Controlling Early Viral Spread in the Periphery and Replication in Neurons. J. Virol. 80: 7009-7019 [Abstract] [Full Text]  
  • Kalamvoki, M., Georgopoulou, U., Mavromara, P. (2006). The NS5A Protein of the Hepatitis C Virus Genotype 1a Is Cleaved by Caspases to Produce C-terminal-truncated Forms of the Protein That Reside Mainly in the Cytosol. J. Biol. Chem. 281: 13449-13462 [Abstract] [Full Text]  
  • Choi, S.-H., Hwang, S. B. (2006). Modulation of the Transforming Growth Factor-beta Signal Transduction Pathway by Hepatitis C Virus Nonstructural 5A Protein. J. Biol. Chem. 281: 7468-7478 [Abstract] [Full Text]  
  • Tellinghuisen, T. L., Marcotrigiano, J., Gorbalenya, A. E., Rice, C. M. (2004). The NS5A Protein of Hepatitis C Virus Is a Zinc Metalloprotein. J. Biol. Chem. 279: 48576-48587 [Abstract] [Full Text]  
  • Sumpter, R. Jr., Wang, C., Foy, E., Loo, Y.-M., Gale, M. Jr. (2004). Viral Evolution and Interferon Resistance of Hepatitis C Virus RNA Replication in a Cell Culture Model. J. Virol. 78: 11591-11604 [Abstract] [Full Text]  
  • Kalamvoki, M., Mavromara, P. (2004). Calcium-Dependent Calpain Proteases Are Implicated in Processing of the Hepatitis C Virus NS5A Protein. J. Virol. 78: 11865-11878 [Abstract] [Full Text]  
  • Bain, C., Parroche, P., Lavergne, J. P., Duverger, B., Vieux, C., Dubois, V., Komurian-Pradel, F., Trepo, C., Gebuhrer, L., Paranhos-Baccala, G., Penin, F., Inchauspe, G. (2004). Memory T-Cell-Mediated Immune Responses Specific to an Alternative Core Protein in Hepatitis C Virus Infection. J. Virol. 78: 10460-10469 [Abstract] [Full Text]  
  • Kaiser, W. J., Kaufman, J. L., Offermann, M. K. (2004). IFN-{alpha} Sensitizes Human Umbilical Vein Endothelial Cells to Apoptosis Induced by Double-Stranded RNA. J. Immunol. 172: 1699-1710 [Abstract] [Full Text]  
  • VYAS, J., ELIA, A., CLEMENS, M. J. (2003). Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA. RNA 9: 858-870 [Abstract] [Full Text]  
  • Schlosser, S. F., Schuler, M., Berg, C. P., Lauber, K., Schulze-Osthoff, K., Schmahl, F. W., Wesselborg, S. (2003). Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells. Antimicrob. Agents Chemother. 47: 1912-1921 [Abstract] [Full Text]  
  • Geiss, G. K., Carter, V. S., He, Y., Kwieciszewski, B. K., Holzman, T., Korth, M. J., Lazaro, C. A., Fausto, N., Bumgarner, R. E., Katze, M. G. (2003). Gene Expression Profiling of the Cellular Transcriptional Network Regulated by Alpha/Beta Interferon and Its Partial Attenuation by the Hepatitis C Virus Nonstructural 5A Protein. J. Virol. 77: 6367-6375 [Abstract] [Full Text]  
  • Tadlock, L., Yamagiwa, Y., Marienfeld, C., Patel, T. (2003). Double-stranded RNA activates a p38 MAPK-dependent cell survival program in biliary epithelia. Am. J. Physiol. Gastrointest. Liver Physiol. 284: G924-G932 [Abstract] [Full Text]  
  • Wang, C., Pflugheber, J., Sumpter, R. Jr., Sodora, D. L., Hui, D., Sen, G. C., Gale, M. Jr. (2003). Alpha Interferon Induces Distinct Translational Control Programs To Suppress Hepatitis C Virus RNA Replication. J. Virol. 77: 3898-3912 [Abstract] [Full Text]  
  • He, Y., Yan, W., Coito, C., Li, Y., Gale, M. Jr, Katze, M. G. (2003). The regulation of hepatitis C virus (HCV) internal ribosome-entry site-mediated translation by HCV replicons and nonstructural proteins. J. Gen. Virol. 84: 535-543 [Abstract] [Full Text]  
  • Rivas-Estilla, A. M., Svitkin, Y., Lopez Lastra, M., Hatzoglou, M., Sherker, A., Koromilas, A. E. (2002). PKR-Dependent Mechanisms of Gene Expression from a Subgenomic Hepatitis C Virus Clone. J. Virol. 76: 10637-10653 [Abstract] [Full Text]  
  • He, Y., Nakao, H., Tan, S.-L., Polyak, S. J., Neddermann, P., Vijaysri, S., Jacobs, B. L., Katze, M. G. (2002). Subversion of Cell Signaling Pathways by Hepatitis C Virus Nonstructural 5A Protein via Interaction with Grb2 and P85 Phosphatidylinositol 3-Kinase. J. Virol. 76: 9207-9217 [Abstract] [Full Text]  
  • Park, K.-J., Choi, S.-H., Lee, S. Y., Hwang, S. B., Lai, M. M. C. (2002). Nonstructural 5A Protein of Hepatitis C Virus Modulates Tumor Necrosis Factor alpha -stimulated Nuclear Factor kappa B Activation. J. Biol. Chem. 277: 13122-13128 [Abstract] [Full Text]  
  • Pflugheber, J., Fredericksen, B., Sumpter, R. Jr., Wang, C., Ware, F., Sodora, D. L., Gale, M. Jr. (2002). Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc. Natl. Acad. Sci. USA 10.1073/pnas.062055699v1 [Abstract] [Full Text]  
  • Ikeda, M., Yi, M., Li, K., Lemon, S. M. (2002). Selectable Subgenomic and Genome-Length Dicistronic RNAs Derived from an Infectious Molecular Clone of the HCV-N Strain of Hepatitis C Virus Replicate Efficiently in Cultured Huh7 Cells. J. Virol. 76: 2997-3006 [Abstract] [Full Text]  
  • Sun, J., Bodola, F., Fan, X., Irshad, H., Soong, L., Lemon, S. M., Chan, T.-S. (2001). Hepatitis C Virus Core and Envelope Proteins Do Not Suppress the Host's Ability To Clear a Hepatic Viral Infection. J. Virol. 75: 11992-11998 [Abstract] [Full Text]  
  • Samuel, C. E. (2001). Antiviral Actions of Interferons. Clin. Microbiol. Rev. 14: 778-809 [Abstract] [Full Text]  
  • Polyak, S. J., Khabar, K. S. A., Paschal, D. M., Ezelle, H. J., Duverlie, G., Barber, G. N., Levy, D. E., Mukaida, N., Gretch, D. R. (2001). Hepatitis C Virus Nonstructural 5A Protein Induces Interleukin-8, Leading to Partial Inhibition of the Interferon-Induced Antiviral Response. J. Virol. 75: 6095-6106 [Abstract] [Full Text]  
  • He, Y., Tan, S.-L., Tareen, S. U., Vijaysri, S., Langland, J. O., Jacobs, B. L., Katze, M. G. (2001). Regulation of mRNA Translation and Cellular Signaling by Hepatitis C Virus Nonstructural Protein NS5A. J. Virol. 75: 5090-5098 [Abstract] [Full Text]  
  • Schweizer, M., Peterhans, E. (2001). Noncytopathic Bovine Viral Diarrhea Virus Inhibits Double-Stranded RNA-Induced Apoptosis and Interferon Synthesis. J. Virol. 75: 4692-4698 [Abstract] [Full Text]  
  • Pitha, P. M. (2001). Latently Expressed Human Herpesvirus 8-Encoded Interferon Regulatory Factor 2 Inhibits Double-Stranded RNA-Activated Protein Kinase. J. Virol. 75: 2345-2352 [Abstract] [Full Text]  
  • Majumder, M., Ghosh, A. K., Steele, R., Ray, R., Ray, R. B. (2001). Hepatitis C Virus NS5A Physically Associates with p53 and Regulates p21/waf1 Gene Expression in a p53-Dependent Manner. J. Virol. 75: 1401-1407 [Abstract] [Full Text]  
  • Lee, J.-Y., Bowden, D. S. (2000). Rubella Virus Replication and Links to Teratogenicity. Clin. Microbiol. Rev. 13: 571-587 [Abstract] [Full Text]  
  • Gale, M. Jr., Tan, S.-L., Katze, M. G. (2000). Translational Control of Viral Gene Expression in Eukaryotes. Microbiol. Mol. Biol. Rev. 64: 239-280 [Abstract] [Full Text]  
  • Ghosh, A. K., Majumder, M., Steele, R., Yaciuk, P., Chrivia, J., Ray, R., Ray, R. B. (2000). Hepatitis C Virus NS5A Protein Modulates Transcription through a Novel Cellular Transcription Factor SRCAP. J. Biol. Chem. 275: 7184-7188 [Abstract] [Full Text]  
  • Liang, T. J., Rehermann, B., Seeff, L. B., Hoofnagle, J. H. (2000). Pathogenesis, Natural History, Treatment, and Prevention of Hepatitis C. ANN INTERN MED 132: 296-305 [Abstract] [Full Text]  
  • Sandres, K., Dubois, M., Pasquier, C., Payen, J. L., Alric, L., Duffaut, M., Vinel, J. P., Pascal, J. P., Puel, J., Izopet, J. (2000). Genetic Heterogeneity of Hypervariable Region 1 of the Hepatitis C Virus (HCV) Genome and Sensitivity of HCV to Alpha Interferon Therapy. J. Virol. 74: 661-668 [Abstract] [Full Text]  
  • Kaufman, R. J. (1999). Double-stranded RNA-activated protein kinase mediates virus-induced apoptosis: A new role for an old actor. Proc. Natl. Acad. Sci. USA 96: 11693-11695 [Full Text]  
  • Pflugheber, J., Fredericksen, B., Sumpter, R. Jr., Wang, C., Ware, F., Sodora, D. L., Gale, M. Jr. (2002). Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc. Natl. Acad. Sci. USA 99: 4650-4655 [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»