Regulation of Interferon Regulatory Factor-3 by the Hepatitis C Virus Serine Protease
Eileen Foy,1
Kui Li,2
Chunfu Wang,1
Rhea Sumpter, Jr.,1
Masanori Ikeda,2
Stanley M. Lemon,2
Michael Gale, Jr.1*
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.
1 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390–9048, USA.
2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555–1019, USA.
* To whom correspondence should be addressed. E-mail: Michael.Gale{at}UTSouthwestern.edu
