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A new survival trick of hepatitis C virus: Blocking the activation of interferon regulatory factor‐3
Author(s) -
Heim Markus H.
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510380632
Subject(s) - ns3 , interferon , ns2 3 protease , hepatitis c virus , virology , viral replication , protease , interferon regulatory factors , serine protease , phosphorylation , biology , effector , virus , irf1 , peptidomimetic , hepacivirus , innate immune system , microbiology and biotechnology , immunology , immune system , enzyme , biochemistry , transcription factor , peptide , gene
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.