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.
| Original language | English |
|---|---|
| Pages (from-to) | 1145-1148 |
| Number of pages | 4 |
| Journal | Science |
| Volume | 300 |
| Issue number | 5622 |
| DOIs | |
| Publication status | Published - May 16 2003 |
| Externally published | Yes |
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Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. / Foy, Eileen; Li, Kui; Wang, Chunfu; Sumpter, Rhea; Ikeda, Masanori; Lemon, Stanley M.; Gale, Michael.
In: Science, Vol. 300, No. 5622, 16.05.2003, p. 1145-1148.Research output: Contribution to journal › Article
}
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
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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UR - http://www.scopus.com/inward/citedby.url?scp=0037687422&partnerID=8YFLogxK
U2 - 10.1126/science.1082604
DO - 10.1126/science.1082604
M3 - Article
VL - 300
SP - 1145
EP - 1148
JO - Science
JF - Science
SN - 0036-8075
IS - 5622
ER -