Foy Eileen, Li Kui, Wang Chunfu, Sumpter Rhea, Ikeda Masanori, Lemon Stanley M, Gale Michael
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9048, USA.
Science. 2003 May 16;300(5622):1145-8. doi: 10.1126/science.1082604. Epub 2003 Apr 17.
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.
丙型肝炎病毒（HCV）的持续感染可能依赖于病毒对宿主防御的抑制。我们发现，HCV NS3/4A丝氨酸蛋白酶可阻断关键细胞抗病毒信号分子干扰素调节因子3（IRF-3）的磷酸化及效应器作用。通过突变或酮酰胺拟肽抑制剂破坏NS3/4A蛋白酶功能可解除这种阻断，并在用无关病毒刺激细胞后恢复IRF-3磷酸化。此外，显性负性或组成型活性IRF-3突变体分别增强或抑制了肝癌细胞中HCV RNA的复制。因此，NS3/4A蛋白酶代表了一个双重治疗靶点，抑制该靶点可能既阻断病毒复制，又恢复IRF-3对HCV感染的控制。
