Institute for Virology, University of Duisburg-Essen, Virchowstrasse 179, 45147 Essen, Germany.
Antiviral Res. 2010 Aug;87(2):272-5. doi: 10.1016/j.antiviral.2010.05.006. Epub 2010 May 19.
The NS3/4A serine protease of the hepatitis C virus (HCV) is one of the most attractive targets for specific antiviral agents. However, mutations conferring resistance may decrease the efficacy of these drugs. Although the level of resistance associated with specific mutations differs between different compounds, substitutions R155K and A156T reduce susceptibility to all protease inhibitors published so far. Interestingly, variants harboring the resistant mutation R155K were also detected as the predominant quasispecies in some treatment-naïve patients. Of note, key positions for resistance overlap with the HLA-A*68-restricted epitope HAVGIFRAAV(1175-1184). The aim of our study was to analyze the impact of protease inhibitor resistance mutations on the replication level and the antiviral CD8 T cell response against this HCV epitope. Our findings suggest that the R155K variant is associated with a relatively high replication level and with a substantial loss of cross-recognition by specific CD8 T cells targeting the epitope HAVGIFRAAV(1175-1184), providing a possible explanation for its existence in the absence of drug selection pressure.
丙型肝炎病毒 (HCV) 的 NS3/4A 丝氨酸蛋白酶是最有吸引力的特定抗病毒药物靶标之一。然而，导致耐药性的突变可能会降低这些药物的疗效。尽管与特定突变相关的耐药水平在不同化合物之间有所不同，但 R155K 和 A156T 取代会降低迄今为止所有已发表的蛋白酶抑制剂的敏感性。有趣的是，含有耐药突变 R155K 的变异体也被检测为一些未经治疗的患者中主要的准种。值得注意的是，耐药的关键位置与 HLA-A*68 限制的表位 HAVGIFRAAV(1175-1184) 重叠。我们的研究旨在分析蛋白酶抑制剂耐药突变对 HCV 表位复制水平和抗病毒 CD8 T 细胞反应的影响。我们的研究结果表明，R155K 变异体与相对较高的复制水平相关，并且与针对 HAVGIFRAAV(1175-1184) 表位的特异性 CD8 T 细胞的交叉识别能力显著丧失，为其在没有药物选择压力的情况下存在提供了可能的解释。
