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Genes 2018, 9(7), 343; https://doi.org/10.3390/genes9070343

Epistatic Interactions in NS5A of Hepatitis C Virus Suggest Drug Resistance Mechanisms

1
Institute of Virology, University of Cologne, 50935 Cologne, Germany
2
German Center for Infection Research (DZIF)—Cologne-Bonn Partner Site, 50935 Cologne, Germany
3
Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany
4
German Center for Infection Research (DZIF)—Saarbrücken Partner Site, 66123 Saarbrücken, Germany
*
Author to whom correspondence should be addressed.
Received: 27 March 2018 / Accepted: 29 June 2018 / Published: 6 July 2018
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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Abstract

Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A resistance-associated mutations (RAMs) have been described at baseline and after therapy failure. A mutation from glutamine to arginine at position 30 (Q30R) is a characteristic RAM for the HCV sub/genotype (GT) 1a, but arginine corresponds to the wild type in the GT-1b; still, GT-1b strains are susceptible to NS5A-inhibitors. In this study, we show that GT-1b strains with R30Q often display other specific NS5A substitutions, particularly in positions 24 and 34. We demonstrate that in GT-1b secondary substitutions usually happen after initial R30Q development in the phylogeny, and that the chemical properties of the corresponding amino acids serve to restore the positive charge in this region, acting as compensatory mutations. These findings may have implications for RAVs treatment. View Full-Text
Keywords: hepatitis C virus; NS5A; drug resistance; epistasis; protein structure hepatitis C virus; NS5A; drug resistance; epistasis; protein structure
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Knops, E.; Sierra, S.; Kalaghatgi, P.; Heger, E.; Kaiser, R.; Kalinina, O.V. Epistatic Interactions in NS5A of Hepatitis C Virus Suggest Drug Resistance Mechanisms. Genes 2018, 9, 343.

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