Hepatitis C Protease Disrupts Immune Defenses

Researchers have found that the NS3/4A serine protease produced by the hepatitis C virus (HCV) blocks the phosphorylation and effector action of interferon regulatory factor-3 (IRF-3), a key cellular antiviral signaling molecule. The lack of antiviral signaling by IRF-3 allows the virus to invade the host and maintain a persistent infection.

Persistent HCV infection is a major cause of liver disease worldwide. To better understand how the virus avoids the immune system's defense mechanisms, investigators from the University of Texas Southwestern Medical Center (Dallas, USA) and the University of Texas Medical Branch (Galveston, USA) worked with liver cells growing in tissue culture. They found that one viral protease, NS3/4A, specifically inhibited a key immune system molecule, IRF-3. Furthermore, they showed that the antiviral activity of IRF-3 was restored when mutation or a ketoamide peptidomimetic inhibitor disrupted the protease function of NS3/4A. These findings were published April 17, 2004, in the online journal ScienceExpress.

The identification of this viral protease-regulated control of IRF-3 opens new avenues in both clinical and basic research on hepatitis C. "Now that we know NS3/4A inhibition essentially restores the host's immune response to the virus, we can assess hepatitis drug candidates for this ability as well,” stated senior author Dr. Michael Gale, assistant professor of microbiology at the UT Southwestern Medical Center.





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University of Texas Southwestern Medical Center