Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage.

Détails

ID Serval
serval:BIB_896F146225B7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage.
Périodique
Journal of Hepatology
Auteur(s)
Welsch C., Haselow K., Gouttenoire J., Schneider M., Morikawa K., Martinez Y., Susser S., Sarrazin C., Zeuzem S., Antes I., Moradpour D., Lange C.M.
ISSN
1600-0641 (Electronic)
ISSN-L
0168-8278
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
62
Numéro
4
Pages
779-784
Langue
anglais
Notes
Publication types: Journal Article Publication Status: ppublish
Résumé
BACKGROUND & AIMS: The hepatitis C virus (HCV) NS3-4A protease is essential for the HCV life cycle and a prime target of antiviral treatment strategies. Protease inhibitors, however, are limited by emergence of resistance-associated amino acid variants (RAVs). The capacity to cleave and inactivate mitochondrial antiviral-signaling protein (MAVS) in the RIG-I-signaling pathway is a cardinal feature of NS3-4A, by which HCV blocks induction of interferon-(IFN)-β, thereby promoting viral persistence. Here, we aimed to investigate the impact of NS3-4A RAVs on MAVS cleavage.
METHODS: The impact of NS3-4A RAVs on MAVS cleavage was assessed using immunoblot analyses, luciferase reporter assays and molecular dynamics simulations to study the underlying molecular principles. IFN-β was quantified in serum from patients with different NS3-4A RAVs.
RESULTS: We show that macrocyclic NS3-4A RAVS with substitutions at residue D168 of the protease result in an increased capacity of NS3-4A to cleave MAVS and suppress IFN-β induction compared with a comprehensive panel of RAVs and wild type HCV. Mechanistically, we show the reconstitution of a tight network of electrostatic interactions between protease and the peptide substrate that allows much stronger binding of MAVS to D168 RAVs than to the wild-type protease. Accordingly, we could show IFN-β serum levels to be lower in patients with treatment failure due to the selection of D168 variants compared to R155 RAVs.
CONCLUSIONS: Our data constitutes a proof of concept that the selection of RAVs against specific classes of direct antivirals can lead to the predominance of viral variants with possibly adverse pathogenic characteristics.
Pubmed
Web of science
Création de la notice
18/04/2015 13:24
Dernière modification de la notice
20/08/2019 15:48
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