TY - JOUR
T1 - Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease
AU - Foy, Eileen
AU - Li, Kui
AU - Wang, Chunfu
AU - Sumpter, Rhea
AU - Ikeda, Masanori
AU - Lemon, Stanley M.
AU - Gale, Michael
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/5/16
Y1 - 2003/5/16
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1082604
DO - 10.1126/science.1082604
M3 - Article
C2 - 12702807
AN - SCOPUS:0037687422
VL - 300
SP - 1145
EP - 1148
JO - Science
JF - Science
SN - 0036-8075
IS - 5622
ER -