Antiviral Suppression vs Restoration of RIG-I Signaling by Hepatitis C Protease and Polymerase Inhibitors

Yuqiong Liang, Hisashi Ishida, Oliver Lenz, Tse I. Lin, Origène Nyanguile, Kenny Simmen, Richard B. Pyles, Nigel Bourne, Min Kyung Yi, Kui Li, Stanley M. Lemon

Research output: Contribution to journalArticle

45 Scopus citations

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-α/β). 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-β 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-β promoter activation but only at concentrations ∼100-fold the antiviral 50% effective concentration (EC50) for genotype 1 virus. No rescue was observed with the polymerase inhibitor, even at a concentration 600-fold greater than the EC50. 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 EC50.

Original languageEnglish (US)
Pages (from-to)1710-1718.e2
JournalGastroenterology
Volume135
Issue number5
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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