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Science 300 (5622): 1145-1148

Copyright © 2003 by the American Association for the Advancement of Science

Regulation of Interferon Regulatory Factor-3 by the Hepatitis C Virus Serine Protease

Eileen Foy,1 Kui Li,2 Chunfu Wang,1 Rhea Sumpter, Jr.,1 Masanori Ikeda,2 Stanley M. Lemon,2 Michael Gale, Jr.1*

Abstract: Persistent infections with hepatitis C virus (HCV) are likely to depend on viral inhibition of host defenses. We show that the HCV NS3/4A serine protease blocks the phosphorylation and effector action of interferon regulatory factor–3 (IRF-3), a key cellular antiviral signaling molecule. Disruption of NS3/4A protease function by mutation or a ketoamide peptidomimetic inhibitor relieved this blockade and restored IRF-3 phosphorylation after cellular challenge with an unrelated virus. Furthermore, dominant-negative or constitutively active IRF-3 mutants, respectively, enhanced or suppressed HCV RNA replication in hepatoma cells. Thus, the NS3/4A protease represents a dual therapeutic target, the inhibition of which may both block viral replication and restore IRF-3 control of HCV infection.

1 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390–9048, USA.
2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555–1019, USA.

* To whom correspondence should be addressed. E-mail: Michael.Gale{at}UTSouthwestern.edu


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Resistance to Alpha/Beta Interferon Is a Determinant of West Nile Virus Replication Fitness and Virulence.
B. C. Keller, B. L. Fredericksen, M. A. Samuel, R. E. Mock, P. W. Mason, M. S. Diamond, and M. Gale Jr. (2006)
J. Virol. 80, 9424-9434
   Abstract »    Full Text »    PDF »
TLR3 Ligation Activates an Antiviral Response in Human Fetal Astrocytes: A Role for Viperin/cig5.
M. A. Rivieccio, H.-S. Suh, Y. Zhao, M.-L. Zhao, K. C. Chin, S. C. Lee, and C. F. Brosnan (2006)
J. Immunol. 177, 4735-4741
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The hepatitis C virus and immune evasion: non-structural 3/4A transgenic mice are resistant to lethal tumour necrosis factor {alpha} mediated liver disease.
L Frelin, E D Brenndorfer, G Ahlen, M Weiland, C Hultgren, M Alheim, H Glaumann, B Rozell, D R Milich, J G Bode, et al. (2006)
Gut 55, 1475-1483
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Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus.
L. Martinez-Sobrido, E. I. Zuniga, D. Rosario, A. Garcia-Sastre, and J. C. de la Torre (2006)
J. Virol. 80, 9192-9199
   Abstract »    Full Text »    PDF »
Antiviral defense: interferons and beyond.
D. B. Stetson and R. Medzhitov (2006)
J. Exp. Med. 203, 1837-1841
   Abstract »    Full Text »    PDF »
Reduced Expression of Toll-Like Receptor 2 on Peripheral Monocytes in Patients with Chronic Hepatitis B.
S. M. Riordan, N. Skinner, J. Kurtovic, S. Locarnini, and K. Visvanathan (2006)
Clin. Vaccine Immunol. 13, 972-974
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Hepatitis C Virus Triggers Mitochondrial Permeability Transition with Production of Reactive Oxygen Species, Leading to DNA Damage and STAT3 Activation.
K. Machida, K. T.-H. Cheng, C.-K. Lai, K.-S. Jeng, V. M.-H. Sung, and M. M. C. Lai (2006)
J. Virol. 80, 7199-7207
   Abstract »    Full Text »    PDF »
Kaposi's sarcoma-associated herpesvirus immune modulation: an overview.
S. A. R. Rezaee, C. Cunningham, A. J. Davison, and D. J. Blackbourn (2006)
J. Gen. Virol. 87, 1781-1804
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NS3 protein of Hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner.
L. Deng, M. Nagano-Fujii, M. Tanaka, Y. Nomura-Takigawa, M. Ikeda, N. Kato, K. Sada, and H. Hotta (2006)
J. Gen. Virol. 87, 1703-1713
   Abstract »    Full Text »    PDF »
Molecular Determinants of Substrate Specificity for Semliki Forest Virus Nonstructural Protease.
A. Lulla, V. Lulla, K. Tints, T. Ahola, and A. Merits (2006)
J. Virol. 80, 5413-5422
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Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms.
G. Cheng, J. Zhong, and F. V. Chisari (2006)
PNAS 103, 8499-8504
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Human Rhinovirus Attenuates the Type I Interferon Response by Disrupting Activation of Interferon Regulatory Factor 3.
T. Peng, S. Kotla, R. E. Bumgarner, and K. E. Gustin (2006)
J. Virol. 80, 5021-5031
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VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells.
K. Lin, R. B. Perni, A. D. Kwong, and C. Lin (2006)
Antimicrob. Agents Chemother. 50, 1813-1822
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Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection.
Y.-M. Loo, D. M. Owen, K. Li, A. K. Erickson, C. L. Johnson, P. M. Fish, D. S. Carney, T. Wang, H. Ishida, M. Yoneyama, et al. (2006)
PNAS 103, 6001-6006
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Mutations Conferring Resistance to SCH6, a Novel Hepatitis C Virus NS3/4A Protease Inhibitor: REDUCED RNA REPLICATION FITNESS AND PARTIAL RESCUE BY SECOND-SITE MUTATIONS.
M. Yi, X. Tong, A. Skelton, R. Chase, T. Chen, A. Prongay, S. L. Bogen, A. K. Saksena, F. G. Njoroge, R. L. Veselenak, et al. (2006)
J. Biol. Chem. 281, 8205-8215
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SCH 503034, a Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease, Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Alpha Interferon in Replicon Cells.
B. A. Malcolm, R. Liu, F. Lahser, S. Agrawal, B. Belanger, N. Butkiewicz, R. Chase, F. Gheyas, A. Hart, D. Hesk, et al. (2006)
Antimicrob. Agents Chemother. 50, 1013-1020
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Activation of anti-hepatitis C virus responses via Toll-like receptor 7.
J. Lee, C. C. N. Wu, K. J. Lee, T.-H. Chuang, K. Katakura, Y.-T. Liu, M. Chan, R. Tawatao, M. Chung, C. Shen, et al. (2006)
PNAS 103, 1828-1833
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Effect of Cell Growth on Hepatitis C Virus (HCV) Replication and a Mechanism of Cell Confluence-Based Inhibition of HCV RNA and Protein Expression.
H. B. Nelson and H. Tang (2006)
J. Virol. 80, 1181-1190
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Relation between viral fitness and immune escape within the hepatitis C virus protease.
J Soderholm, G Ahlen, A Kaul, L Frelin, M Alheim, C Barnfield, P Liljestrom, O Weiland, D R Milich, R Bartenschlager, et al. (2006)
Gut 55, 266-274
   Abstract »    Full Text »    PDF »

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