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Restoration of the activated Rig-I pathway in hepatitis C virus (HCV) replicon cells by HCV protease, polymerase, and NS5A inhibitors in vitro at clinically relevant concentrations

Kalkeri, G and Lin, C and Gopilan, J and Sloan, K and Rijnbrand, R and Kwong, AD (2013) Restoration of the activated Rig-I pathway in hepatitis C virus (HCV) replicon cells by HCV protease, polymerase, and NS5A inhibitors in vitro at clinically relevant concentrations. Antimicrobial Agents and Chemotherapy. pp. 4417-4426.

Abstract

Development of persistent hepatitis C virus (HCV) infection may be mediated by HCV NS3 4A protease-dependent inhibition of host innate immunity. When double-stranded RNA (dsRNA) is detected in virus-infected cells, host innate immunity mounts an antiviral response by upregulating production of type I interferons (alpha/beta interferon [IFN-alpha/beta]); HCV counters by cleaving the IFN-beta stimulator 1 (IPS-1) adaptor protein, decreasing synthesis of IFN-alpha/beta. We evaluated HCV protease (telaprevir, boceprevir, and TMC435350), polymerase (HCV-796 and VX-222), and NS5A (BMS-790052) inhibitors for the ability to restore IPS-1-mediated Rig-I signaling by measuring Sendai virus-induced IFN-beta promoter activation in HCV replicon cells after various exposure durations. All direct-acting HCV antivirals tested restored mitochondrial localization of IPS-1 and rescued Sendai virusinduced IRF3 signaling after 7 days by inhibiting HCV replication, thereby reducing the abundance of HCV NS3 4A protease. With 4-day treatment, HCV protease inhibitors, but not polymerase inhibitors, restored mitochondrial localization of IPS-1 and rescued IFN-beta promoter activation in the presence of equivalent levels of NS3 protein in protease or polymerase inhibitortreated cells. The concentrations of HCV protease and polymerase inhibitors needed to rescue IRF3-mediated signaling in vitro were in the range of those observed in vivo in the plasma of treated HCV patients. These findings suggest that (i) HCV protease, polymerase, and NS5A inhibitors can restore virus-induced IRF3 signaling by inhibiting viral replication, thereby reducing NS3 protease levels, and (ii) HCV protease inhibitors can restore innate immunity by directly inhibiting NS3 protease-mediated cleavage of IPS-1 at clinically achievable concentrations. Copyright 2013, American Society for Microbiology. All Rights Reserved

Item Type: Article
Additional Information: pubid: 192 nvp_institute: NIBR contributor_address: (Kalkeri, Lin, Gopilan, Sloan, Rijnbrand, Kwong) Vertex Pharmaceuticals Incorporated, Cambridge, MA, United States (Gopilan) Communispace, Boston, MA, United States (Sloan) Novartis Institutes for BioMedical Research, Cambridge, MA, United States (Kwong) InnovaTID, Cambridge, MA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22013

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