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

被引：12

作者：

Knops, Elena ^{[1
]}

Sierra, Saleta ^{[1
,2
]}

Kalaghatgi, Prabhav ^{[3
,4
]}

Heger, Eva ^{[1
]}

Kaiser, Rolf ^{[1
,2
]}

Kalinina, Olga, V ^{[3
]}

机构：

[1] Univ Cologne, Inst Virol, D-50935 Cologne, Germany

[2] German Ctr Infect Res DZIF, Cologne Bonn Partner Site, D-50935 Cologne, Germany

[3] Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, D-66123 Saarbrucken, Germany

[4] German Ctr Infect Res DZIF, Saarbrucken Partner Site, D-66123 Saarbrucken, Germany

来源：

GENES | 2018年 / 9卷 / 07期

关键词：

hepatitis C virus; NS5A; drug resistance; epistasis; protein structure; GENOTYPE; 1; INFECTION; COMPENSATORY MUTATIONS; PLUS RIBAVIRIN; PARITAPREVIR-RITONAVIR; COMBINATION THERAPY; NATURAL PREVALENCE; CRYSTAL-STRUCTURE; HCV; VARIANTS; DOMAIN;

D O I：

10.3390/genes9070343

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：16