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Journal of Virology, February 2000, p. 2046-2051, Vol. 74, No. 4
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hepatitis C Virus-Encoded Enzymatic Activities and Conserved RNA Elements in the 3' Nontranslated Region Are Essential for Virus Replication In Vivo

Alexander A. Kolykhalov,1 Kathy Mihalik,2 Stephen M. Feinstone,2 and Charles M. Rice1,*

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110-1093,1 and Division of Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208922

Received 7 July 1999/Accepted 22 November 1999

Hepatitis C virus (HCV) infection is a widespread major human health concern. Significant obstacles in the study of this virus include the absence of a reliable tissue culture system and a small-animal model. Recently, we constructed full-length HCV cDNA clones and successfully initiated HCV infection in two chimpanzees by intrahepatic injection of in vitro-transcribed RNA (A. A. Kolykhalov et al., Science 277:570-574, 1997). In order to validate potential targets for development of anti-HCV therapeutics, we constructed six mutant derivatives of this prototype infectious clone. Four clones contained point mutations ablating the activity of the NS2-3 protease, the NS3-4A serine protease, the NS3 NTPase/helicase, and the NS5B polymerase. Two additional clones contained deletions encompassing all or part of the highly conserved 98-base sequence at the 3' terminus of the HCV genome RNA. The RNA transcript from each of the six clones was injected intrahepatically into a chimpanzee. No signs of HCV infection were detected in the 8 months following the injection. Inoculation of the same animal with nonmutant RNA transcripts resulted in productive HCV infection, as evidenced by viremia, elevated serum alanine aminotransferase, and HCV-specific seroconversion. These data suggest that these four HCV-encoded enzymatic activities and the conserved 3' terminal RNA element are essential for productive replication in vivo.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Campus Box 8230, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110-1093. Phone: (314) 362-2842. Fax: (314) 362-1232. E-mail: rice{at}borcim.wustl.edu.

Journal of Virology, February 2000, p. 2046-2051, Vol. 74, No. 4
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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  • Blight, K. J., McKeating, J. A., Marcotrigiano, J., Rice, C. M. (2003). Efficient Replication of Hepatitis C Virus Genotype 1a RNAs in Cell Culture. J. Virol. 77: 3181-3190 [Abstract] [Full Text]  
  • Dumas, E., Staedel, C., Colombat, M., Reigadas, S., Chabas, S., Astier-Gin, T., Cahour, A., Litvak, S., Ventura, M. (2003). A promoter activity is present in the DNA sequence corresponding to the hepatitis C virus 5' UTR. Nucleic Acids Res 31: 1275-1281 [Abstract] [Full Text]  
  • Piccininni, S., Varaklioti, A., Nardelli, M., Dave, B., Raney, K. D., McCarthy, J. E. G. (2002). Modulation of the Hepatitis C Virus RNA-dependent RNA Polymerase Activity by the Non-Structural (NS) 3 Helicase and the NS4B Membrane Protein. J. Biol. Chem. 277: 45670-45679 [Abstract] [Full Text]  
  • Bukh, J., Pietschmann, T., Lohmann, V., Krieger, N., Faulk, K., Engle, R. E., Govindarajan, S., Shapiro, M., St. Claire, M., Bartenschlager, R. (2002). Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees. Proc. Natl. Acad. Sci. USA 99: 14416-14421 [Abstract] [Full Text]  
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  • 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]  
  • Smith, R. M., Walton, C. M., Wu, C. H., Wu, G. Y. (2002). Secondary Structure and Hybridization Accessibility of Hepatitis C Virus 3'-Terminal Sequences. J. Virol. 76: 9563-9574 [Abstract] [Full Text]  
  • Levin, M. K., Patel, S. S. (2002). Helicase from Hepatitis C Virus, Energetics of DNA Binding. J. Biol. Chem. 277: 29377-29385 [Abstract] [Full Text]  
  • Kashiwagi, T., Hara, K., Kohara, M., Iwahashi, J., Hamada, N., Honda-Yoshino, H., Toyoda, T. (2002). Promoter/Origin Structure of the Complementary Strand of Hepatitis C Virus Genome. J. Biol. Chem. 277: 28700-28705 [Abstract] [Full Text]  
  • Schuster, C., Isel, C., Imbert, I., Ehresmann, C., Marquet, R., Kieny, M. P. (2002). Secondary Structure of the 3' Terminus of Hepatitis C Virus Minus-Strand RNA. J. Virol. 76: 8058-8068 [Abstract] [Full Text]  
  • Tardif, K. D., Mori, K., Siddiqui, A. (2002). Hepatitis C Virus Subgenomic Replicons Induce Endoplasmic Reticulum Stress Activating an Intracellular Signaling Pathway. J. Virol. 76: 7453-7459 [Abstract] [Full Text]  
  • Major, M. E., Mihalik, K., Puig, M., Rehermann, B., Nascimbeni, M., Rice, C. M., Feinstone, S. M. (2002). Previously Infected and Recovered Chimpanzees Exhibit Rapid Responses That Control Hepatitis C Virus Replication upon Rechallenge. J. Virol. 76: 6586-6595 [Abstract] [Full Text]  
  • Friebe, P., Bartenschlager, R. (2002). Genetic Analysis of Sequences in the 3' Nontranslated Region of Hepatitis C Virus That Are Important for RNA Replication. J. Virol. 76: 5326-5338 [Abstract] [Full Text]  
  • Wang, Q. M., Hockman, M. A., Staschke, K., Johnson, R. B., Case, K. A., Lu, J., Parsons, S., Zhang, F., Rathnachalam, R., Kirkegaard, K., Colacino, J. M. (2002). Oligomerization and Cooperative RNA Synthesis Activity of Hepatitis C Virus RNA-Dependent RNA Polymerase. J. Virol. 76: 3865-3872 [Abstract] [Full Text]  
  • Pietschmann, T., Lohmann, V., Kaul, A., Krieger, N., Rinck, G., Rutter, G., Strand, D., Bartenschlager, R. (2002). Persistent and Transient Replication of Full-Length Hepatitis C Virus Genomes in Cell Culture. J. Virol. 76: 4008-4021 [Abstract] [Full Text]  
  • Moradpour, D., Bieck, E., Hugle, T., Wels, W., Wu, J. Z., Hong, Z., Blum, H. E., Bartenschlager, R. (2002). Functional Properties of a Monoclonal Antibody Inhibiting the Hepatitis C Virus RNA-dependent RNA Polymerase. J. Biol. Chem. 277: 593-601 [Abstract] [Full Text]  


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