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Gastroenterology. 2008 Nov;135(5):1710-1718.e2. doi: 10.1053/j.gastro.2008.07.023. Epub 2008 Jul 22.

Antiviral suppression vs restoration of RIG-I signaling by hepatitis C protease and polymerase inhibitors.

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  • 1Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555-1073, USA.

Abstract

BACKGROUND & AIMS:

Expression of the nonstructural protein (NS)3/4A protease in cells infected with hepatitis C virus (HCV) results in cleavage of the mitochondrial antiviral-signaling protein (MAVS) and disruption of signaling pathways that lead to viral activation of interferon regulatory factor 3 (IRF-3) and synthesis of type 1 interferons (IFN-alpha/beta). High concentrations of inhibitors of NS3/4A reverse this signaling defect, but quantitative analyses of this potential therapeutic effect are lacking. This study quantitatively assessed the rescue of IRF-3 signaling by NS3/4A inhibitors, compared with in vitro antiviral activity.

METHODS:

Antiviral activities of 2 NS3/4A protease inhibitors (TMC435350 and an analog, TMC380765) and a nonnucleoside polymerase inhibitor (Tib-3) were determined in HCV replicon cells and in cells infected with genotype 1a and 2a viruses. The capacity to rescue IRF-3 activation in these cells was assessed by monitoring IFN-beta promoter activity following challenge with Sendai virus. Inhibitor-induced changes in NS3 and MAVS expression were assessed in immunoblots.

RESULTS:

Both protease inhibitors were capable of rescuing IFN-beta promoter activation but only at concentrations approximately 100-fold the antiviral 50% effective concentration (EC(50)) for genotype 1 virus. No rescue was observed with the polymerase inhibitor, even at a concentration 600-fold greater than the EC(50). IRF-3 activation did not correlate with reductions in NS3/4A levels or detection of full-length MAVS. Overexpression of the product of NS3/4A cleavage of MAVS did not result in a dominant-negative effect on signaling.

CONCLUSIONS:

NS3/4A protease inhibitors can restore IRF-3 signaling in HCV-infected cells but only at concentrations far in excess of the antiviral EC(50).

PMID:
18725224
DOI:
10.1053/j.gastro.2008.07.023
[PubMed - indexed for MEDLINE]
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