Knops Elena, Sierra Saleta, Kalaghatgi Prabhav, Heger Eva, Kaiser Rolf, Kalinina Olga V
Institute of Virology, University of Cologne, 50935 Cologne, Germany.
German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, 50935 Cologne, Germany.
Genes (Basel). 2018 Jul 6;9(7):343. doi: 10.3390/genes9070343.
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.
丙型肝炎病毒（HCV）造成了重大的健康负担，而直接抗病毒药物（DAA）可有效治疗该疾病。非结构蛋白5A（NS5A）在病毒基因组复制中发挥作用，是DAA的靶点之一。携带NS5A耐药相关突变（RAM）的耐药相关病毒（RAV）在基线期和治疗失败后均有报道。第30位密码子由谷氨酰胺突变为精氨酸（Q30R）是HCV基因亚型/基因型（GT）1a的特征性RAM，但在GT-1b中精氨酸为野生型；尽管如此，GT-1b毒株对NS5A抑制剂仍敏感。在本研究中，我们发现具有R30Q突变的GT-1b毒株通常还会出现其他特定的NS5A替换，尤其是在第24和34位密码子。我们证明，在系统发育过程中，GT-1b中的二级替换通常在最初出现R30Q之后发生，并且相应氨基酸的化学性质有助于恢复该区域的正电荷，起到补偿性突变的作用。这些发现可能对RAV的治疗有影响。
