Antiviral suppression vs restoration of RIG-I signaling by hepatitis C protease and polymerase inhibitors
| Autor: | Min Kyung Yi, Oliver Lenz, Kenny Simmen, Tse I. Lin, Stanley M. Lemon, Richard B. Pyles, Yuqiong Liang, Nigel Bourne, Hisashi Ishida, Kui Li, Origène Nyanguile |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Genotype
viruses medicine.medical_treatment Hepatitis C virus Immunoblotting Hepacivirus Biology Viral Nonstructural Proteins medicine.disease_cause Virus Cell Line DEAD-box RNA Helicases Interferon Simeprevir medicine Humans Protease Inhibitors Receptors Immunologic Adaptor Proteins Signal Transducing NS3 Sulfonamides Protease Hepatology RIG-I Gastroenterology Interferon-beta Hepatitis C Chronic Virology NS2-3 protease Hepatocytes DEAD Box Protein 58 Interferon Regulatory Factor-3 Heterocyclic Compounds 3-Ring Interferon regulatory factors medicine.drug Signal Transduction |
| Zdroj: | Gastroenterology. 135(5) |
| ISSN: | 1528-0012 |
| Popis: | 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 (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 . |
| Databáze: | OpenAIRE |
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