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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation
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Gene Expression Regulation, Viral
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Hepacivirus / enzymology
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Hepacivirus / immunology
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Hepacivirus / physiology*
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Hepatitis C / therapy
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Hepatitis C / virology
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Humans
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Interferon Regulatory Factor-3
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Interferons / biosynthesis
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Interferons / genetics
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Mutation
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Phosphorylation
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Protease Inhibitors / pharmacology
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RNA, Viral / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Serine Endopeptidases / metabolism*
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Viral Nonstructural Proteins / antagonists & inhibitors
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Viral Nonstructural Proteins / metabolism*
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Virus Replication
Substances
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DNA-Binding Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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NS3 protein, hepatitis C virus
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Protease Inhibitors
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RNA, Viral
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RNA-Binding Proteins
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Transcription Factors
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Viral Nonstructural Proteins
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Interferons
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Serine Endopeptidases