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Persistent infections with hepatitis C virus (HCV) are likelyto depend on viral inhibition of host defenses. We show thatthe HCV NS3/4A serine protease blocks the phosphorylation andeffector action of interferon regulatory factor–3 (IRF-3),a key cellular antiviral signaling molecule. Disruption of NS3/4Aprotease function by mutation or a ketoamide peptidomimeticinhibitor relieved this blockade and restored IRF-3 phosphorylationafter 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 andrestore 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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Gut
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PNAS
103, 6001-6006
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PNAS
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From the Cover: Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.
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PNAS
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PNAS
102, 13640-13645
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Dengue Virus Inhibits Alpha Interferon Signaling by Reducing STAT2 Expression.
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|Abstract »|Full Text »|PDF »
Inhibition of RIG-I-Dependent Signaling to the Interferon Pathway during Hepatitis C Virus Expression and Restoration of Signaling by IKK{varepsilon}.
A. Breiman, N. Grandvaux, R. Lin, C. Ottone, S. Akira, M. Yoneyama, T. Fujita, J. Hiscott, and E. F. Meurs (2005)
J. Virol.
79, 3969-3978
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Regulating Intracellular Antiviral Defense and Permissiveness to Hepatitis C Virus RNA Replication through a Cellular RNA Helicase, RIG-I.
R. Sumpter Jr., Y.-M. Loo, E. Foy, K. Li, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale Jr. (2005)
J. Virol.
79, 2689-2699
|Abstract »|Full Text »|PDF »
Establishment of a Subgenomic Replicon for Bovine Viral Diarrhea Virus in Huh-7 Cells and Modulation of Interferon-Regulated Factor 3-Mediated Antiviral Response.
N. Horscroft, D. Bellows, I. Ansari, V. C. H. Lai, S. Dempsey, D. Liang, R. Donis, W. Zhong, and Z. Hong (2005)
J. Virol.
79, 2788-2796
|Abstract »|Full Text »|PDF »
Interferon Regulatory Factor 3-Independent Double-Stranded RNA-Induced Inhibition of Hepatitis C Virus Replicons in Human Embryonic Kidney 293 Cells.
Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling.
E. Foy, K. Li, R. Sumpter Jr., Y.-M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, et al. (2005)
PNAS
102, 2986-2991
|Abstract »|Full Text »|PDF »
Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF.
K. Li, E. Foy, J. C. Ferreon, M. Nakamura, A. C. M. Ferreon, M. Ikeda, S. C. Ray, M. Gale Jr., and S. M. Lemon (2005)
PNAS
102, 2992-2997
|Abstract »|Full Text »|PDF »
Inhibition of Interferon Signaling by the New York 99 Strain and Kunjin Subtype of West Nile Virus Involves Blockage of STAT1 and STAT2 Activation by Nonstructural Proteins.
W. J. Liu, X. J. Wang, V. V. Mokhonov, P.-Y. Shi, R. Randall, and A. A. Khromykh (2005)
J. Virol.
79, 1934-1942
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Intrahepatic Gene Expression during Chronic Hepatitis C Virus Infection in Chimpanzees.
C. B. Bigger, B. Guerra, K. M. Brasky, G. Hubbard, M. R. Beard, B. A. Luxon, S. M. Lemon, and R. E. Lanford (2004)
J. Virol.
78, 13779-13792
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Combination of a Hepatitis C Virus NS3-NS4A Protease Inhibitor and Alpha Interferon Synergistically Inhibits Viral RNA Replication and Facilitates Viral RNA Clearance in Replicon Cells.
K. Lin, A. D. Kwong, and C. Lin (2004)
Antimicrob. Agents Chemother.
48, 4784-4792
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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.
W. J. Liu, H. B. Chen, X. J. Wang, H. Huang, and A. A. Khromykh (2004)
J. Virol.
78, 12225-12235
|Abstract »|Full Text »|PDF »
Genetic diversity and evolution of hepatitis C virus - 15 years on.
Viral Evolution and Interferon Resistance of Hepatitis C Virus RNA Replication in a Cell Culture Model.
R. Sumpter Jr., C. Wang, E. Foy, Y.-M. Loo, and M. Gale Jr. (2004)
J. Virol.
78, 11591-11604
|Abstract »|Full Text »|PDF »
Major Human Cytomegalovirus Structural Protein pp65 (ppUL83) Prevents Interferon Response Factor 3 Activation in the Interferon Response.
D. A. Abate, S. Watanabe, and E. S. Mocarski (2004)
J. Virol.
78, 10995-11006
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Memory T-Cell-Mediated Immune Responses Specific to an Alternative Core Protein in Hepatitis C Virus Infection.
C. Bain, P. Parroche, J. P. Lavergne, B. Duverger, C. Vieux, V. Dubois, F. Komurian-Pradel, C. Trepo, L. Gebuhrer, G. Paranhos-Baccala, et al. (2004)
J. Virol.
78, 10460-10469
|Abstract »|Full Text »|PDF »
Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis.
