This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhu, Q. Articles by Seeger, C. Search for Related Content PubMed PubMed Citation Articles by Zhu, Q. Articles by Seeger, C.

Replication of Hepatitis C Virus Subgenomes in Nonhepatic Epithelial and Mouse Hepatoma Cells

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

Received 8 April 2003/ Accepted 30 May 2003

The hepatitis C virus (HCV) pandemic affects the health of more than 170 million people and is the major indication for orthotopic liver transplantations. Although the human liver is the primary site for HCV replication, it is not known whether extrahepatic tissues are also infected by the virus and whether nonprimate cells are permissive for RNA replication. Because HCV exists as a quasispecies, it is conceivable that a viral population may include variants that can replicate in different cell types and in other species. We have tested this hypothesis and found that subgenomic HCV RNAs can replicate in mouse hepatoma and nonhepatic human epithelial cells. Replicons isolated from these cell lines carry new mutations that could be involved in the control of tropism of the virus. Our results demonstrated that translation and RNA-directed RNA replication of HCV do not depend on hepatocyte or primate-specific factors. Moreover, our results could open the path for the development of animal models for HCV infection.

This article has been cited by other articles:

• Jiang, D., Guo, H., Xu, C., Chang, J., Gu, B., Wang, L., Block, T. M., Guo, J.-T. (2008). Identification of Three Interferon-Inducible Cellular Enzymes That Inhibit the Replication of Hepatitis C Virus. J. Virol. 82: 1665-1678 [Abstract] [Full Text]  
• Tellinghuisen, T. L., Foss, K. L., Treadaway, J. C., Rice, C. M. (2008). Identification of Residues Required for RNA Replication in Domains II and III of the Hepatitis C Virus NS5A Protein. J. Virol. 82: 1073-1083 [Abstract] [Full Text]  
• Tasaka, M., Sakamoto, N., Itakura, Y., Nakagawa, M., Itsui, Y., Sekine-Osajima, Y., Nishimura-Sakurai, Y., Chen, C.-H., Yoneyama, M., Fujita, T., Wakita, T., Maekawa, S., Enomoto, N., Watanabe, M. (2007). Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response. J. Gen. Virol. 88: 3323-3333 [Abstract] [Full Text]  
• Lindenbach, B. D., Pragai, B. M., Montserret, R., Beran, R. K. F., Pyle, A. M., Penin, F., Rice, C. M. (2007). The C Terminus of Hepatitis C Virus NS4A Encodes an Electrostatic Switch That Regulates NS5A Hyperphosphorylation and Viral Replication. J. Virol. 81: 8905-8918 [Abstract] [Full Text]  
• Randall, G., Panis, M., Cooper, J. D., Tellinghuisen, T. L., Sukhodolets, K. E., Pfeffer, S., Landthaler, M., Landgraf, P., Kan, S., Lindenbach, B. D., Chien, M., Weir, D. B., Russo, J. J., Ju, J., Brownstein, M. J., Sheridan, R., Sander, C., Zavolan, M., Tuschl, T., Rice, C. M. (2007). Cellular cofactors affecting hepatitis C virus infection and replication. Proc. Natl. Acad. Sci. USA 104: 12884-12889 [Abstract] [Full Text]  
• Huang, H., Sun, F., Owen, D. M., Li, W., Chen, Y., Gale, M. Jr., Ye, J. (2007). From the Cover: Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins. Proc. Natl. Acad. Sci. USA 104: 5848-5853 [Abstract] [Full Text]  
• Dahari, H., Ribeiro, R. M., Rice, C. M., Perelson, A. S. (2007). Mathematical Modeling of Subgenomic Hepatitis C Virus Replication in Huh-7 Cells. J. Virol. 81: 750-760 [Abstract] [Full Text]  
• Koutsoudakis, G., Herrmann, E., Kallis, S., Bartenschlager, R., Pietschmann, T. (2007). The Level of CD81 Cell Surface Expression Is a Key Determinant for Productive Entry of Hepatitis C Virus into Host Cells. J. Virol. 81: 588-598 [Abstract] [Full Text]  
• Lundin, M., Lindstrom, H., Gronwall, C., Persson, M. A. A. (2006). Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein.. J. Gen. Virol. 87: 3263-3272 [Abstract] [Full Text]  
• Chang, K.-S., Cai, Z., Zhang, C., Sen, G. C., Williams, B. R. G., Luo, G. (2006). Replication of Hepatitis C Virus (HCV) RNA in Mouse Embryonic Fibroblasts: Protein Kinase R (PKR)-Dependent and PKR-Independent Mechanisms for Controlling HCV RNA Replication and Mediating Interferon Activities.. J. Virol. 80: 7364-7374 [Abstract] [Full Text]  
• Gudima, S. O., Chang, J., Taylor, J. M. (2006). Restoration in vivo of defective hepatitis delta virus RNA genomes. RNA 12: 1061-1073 [Abstract] [Full Text]  
• Liu, S., Ansari, I. H., Das, S. C., Pattnaik, A. K. (2006). Insertion and deletion analyses identify regions of non-structural protein 5A of Hepatitis C virus that are dispensable for viral genome replication. J. Gen. Virol. 87: 323-327 [Abstract] [Full Text]  
• Nelson, H. B., Tang, H. (2006). Effect of Cell Growth on Hepatitis C Virus (HCV) Replication and a Mechanism of Cell Confluence-Based Inhibition of HCV RNA and Protein Expression. J. Virol. 80: 1181-1190 [Abstract] [Full Text]  
• Windisch, M. P., Frese, M., Kaul, A., Trippler, M., Lohmann, V., Bartenschlager, R. (2005). Dissecting the Interferon-Induced Inhibition of Hepatitis C Virus Replication by Using a Novel Host Cell Line. J. Virol. 79: 13778-13793 [Abstract] [Full Text]  
• Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M., Sarnow, P. (2005). Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA. Science 309: 1577-1581 [Abstract] [Full Text]  
• Ludmerer, S. W., Graham, D. J., Boots, E., Murray, E. M., Simcoe, A., Markel, E. J., Grobler, J. A., Flores, O. A., Olsen, D. B., Hazuda, D. J., LaFemina, R. L. (2005). Replication Fitness and NS5B Drug Sensitivity of Diverse Hepatitis C Virus Isolates Characterized by Using a Transient Replication Assay. Antimicrob. Agents Chemother. 49: 2059-2069 [Abstract] [Full Text]  
• Li, K., Chen, Z., Kato, N., Gale, M. Jr., Lemon, S. M. (2005). Distinct Poly(I-C) and Virus-activated Signaling Pathways Leading to Interferon-{beta} Production in Hepatocytes. J. Biol. Chem. 280: 16739-16747 [Abstract] [Full Text]  
• Breiman, A., Grandvaux, N., Lin, R., Ottone, C., Akira, S., Yoneyama, M., Fujita, T., Hiscott, J., Meurs, E. F. (2005). Inhibition of RIG-I-Dependent Signaling to the Interferon Pathway during Hepatitis C Virus Expression and Restoration of Signaling by IKK{varepsilon}. J. Virol. 79: 3969-3978 [Abstract] [Full Text]  
• Kato, N., Nakamura, T., Dansako, H., Namba, K., Abe, K.-i., Nozaki, A., Naka, K., Ikeda, M., Shimotohno, K. (2005). Genetic variation and dynamics of hepatitis C virus replicons in long-term cell culture. J. Gen. Virol. 86: 645-656 [Abstract] [Full Text]  
• Appel, N., Pietschmann, T., Bartenschlager, R. (2005). Mutational Analysis of Hepatitis C Virus Nonstructural Protein 5A: Potential Role of Differential Phosphorylation in RNA Replication and Identification of a Genetically Flexible Domain. J. Virol. 79: 3187-3194 [Abstract] [Full Text]  
• Li, K., Foy, E., Ferreon, J. C., Nakamura, M., Ferreon, A. C. M., Ikeda, M., Ray, S. C., Gale, M. Jr., Lemon, S. M. (2005). Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. USA 102: 2992-2997 [Abstract] [Full Text]  
• Pfeiffer, J. K., Kirkegaard, K. (2005). Ribavirin Resistance in Hepatitis C Virus Replicon-Containing Cell Lines Conferred by Changes in the Cell Line or Mutations in the Replicon RNA. J. Virol. 79: 2346-2355 [Abstract] [Full Text]  
• Guo, J.-T., Hayashi, J., Seeger, C. (2005). West Nile Virus Inhibits the Signal Transduction Pathway of Alpha Interferon. J. Virol. 79: 1343-1350 [Abstract] [Full Text]  
• Friebe, P., Boudet, J., Simorre, J.-P., Bartenschlager, R. (2005). Kissing-Loop Interaction in the 3' End of the Hepatitis C Virus Genome Essential for RNA Replication. J. Virol. 79: 380-392 [Abstract] [Full Text]  
• Kato, T., Date, T., Miyamoto, M., Zhao, Z., Mizokami, M., Wakita, T. (2005). Nonhepatic Cell Lines HeLa and 293 Support Efficient Replication of the Hepatitis C Virus Genotype 2a Subgenomic Replicon. J. Virol. 79: 592-596 [Abstract] [Full Text]  
• Kim, S.-J., Kim, J.-H., Kim, Y.-G., Lim, H.-S., Oh, J.-W. (2004). Protein Kinase C-related Kinase 2 Regulates Hepatitis C Virus RNA Polymerase Function by Phosphorylation. J. Biol. Chem. 279: 50031-50041 [Abstract] [Full Text]  
• Liu, W. J., Chen, H. B., Wang, X. J., Huang, H., Khromykh, A. A. (2004). Analysis of Adaptive Mutations in Kunjin Virus Replicon RNA Reveals a Novel Role for the Flavivirus Nonstructural Protein NS2A in Inhibition of Beta Interferon Promoter-Driven Transcription. J. Virol. 78: 12225-12235 [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]  
• Kanazawa, N., Kurosaki, M., Sakamoto, N., Enomoto, N., Itsui, Y., Yamashiro, T., Tanabe, Y., Maekawa, S., Nakagawa, M., Chen, C.-H., Kakinuma, S., Oshima, S., Nakamura, T., Kato, T., Wakita, T., Watanabe, M. (2004). Regulation of Hepatitis C Virus Replication by Interferon Regulatory Factor 1. J. Virol. 78: 9713-9720 [Abstract] [Full Text]  
• Macdonald, A., Harris, M. (2004). Hepatitis C virus NS5A: tales of a promiscuous protein. J. Gen. Virol. 85: 2485-2502 [Abstract] [Full Text]  
• Deforges, S., Evlashev, A., Perret, M., Sodoyer, M., Pouzol, S., Scoazec, J.-Y., Bonnaud, B., Diaz, O., Paranhos-Baccala, G., Lotteau, V., Andre, P. (2004). Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo. J. Gen. Virol. 85: 2515-2523 [Abstract] [Full Text]  
• Yi, M., Lemon, S. M. (2004). Adaptive Mutations Producing Efficient Replication of Genotype 1a Hepatitis C Virus RNA in Normal Huh7 Cells. J. Virol. 78: 7904-7915 [Abstract] [Full Text]  
• Moradpour, D., Evans, M. J., Gosert, R., Yuan, Z., Blum, H. E., Goff, S. P., Lindenbach, B. D., Rice, C. M. (2004). Insertion of Green Fluorescent Protein into Nonstructural Protein 5A Allows Direct Visualization of Functional Hepatitis C Virus Replication Complexes. J. Virol. 78: 7400-7409 [Abstract] [Full Text]  
• Date, T., Kato, T., Miyamoto, M., Zhao, Z., Yasui, K., Mizokami, M., Wakita, T. (2004). Genotype 2a Hepatitis C Virus Subgenomic Replicon Can Replicate in HepG2 and IMY-N9 Cells. J. Biol. Chem. 279: 22371-22376 [Abstract] [Full Text]  
• Wieland, S. F., Spangenberg, H. C., Thimme, R., Purcell, R. H., Chisari, F. V. (2004). Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc. Natl. Acad. Sci. USA 101: 2129-2134 [Abstract] [Full Text]  
• McCormick, C. J., Challinor, L., Macdonald, A., Rowlands, D. J., Harris, M. (2004). Introduction of replication-competent hepatitis C virus transcripts using a tetracycline-regulable baculovirus delivery system. J. Gen. Virol. 85: 429-439 [Abstract] [Full Text]  
• Ali, S., Pellerin, C., Lamarre, D., Kukolj, G. (2004). Hepatitis C Virus Subgenomic Replicons in the Human Embryonic Kidney 293 Cell Line. J. Virol. 78: 491-501 [Abstract] [Full Text]  
• Guo, J.-T., Zhu, Q., Seeger, C. (2003). Cytopathic and Noncytopathic Interferon Responses in Cells Expressing Hepatitis C Virus Subgenomic Replicons. J. Virol. 77: 10769-10779 [Abstract] [Full Text]