Ikram Aqsa, Obaid Ayesha, Awan Faryal Mehwish, Hanif Rumeza, Naz Anam, Paracha Rehan Zafar, Ali Amjad, Janjua Hussnain Ahmed
Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
Department of Healtcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
Antiviral Res. 2017 Jan;137:112-124. doi: 10.1016/j.antiviral.2016.10.013. Epub 2016 Oct 28.
Cellular immune responses (T cell responses) during hepatitis C virus (HCV) infection are significant factors for determining the outcome of infection. HCV adapts to host immune responses by inducing mutations in its genome at specific sites that are important for HLA processing/presentation. Moreover, HCV also adapts to resist potential drugs that are used to restrict its replication, such as direct-acting antivirals (DAAs). Although DAAs have significantly reduced disease burden, resistance to these drugs is still a challenge for the treatment of HCV infection. Recently, drug resistance mutations (DRMs) observed in HCV proteins (NS3/4A, NS5A and NS5B) have heightened concern that the emergence of drug resistance may compromise the effectiveness of DAAs. Therefore, the NS3/4A, NS5A and NS5B drug resistance variations were investigated in this study, and their prevalence was examined in a large number of protein sequences from all HCV genotypes. Furthermore, potential CD4 and CD8 T cell epitopes were predicted and their overlap with genetic variations was explored. The findings revealed that many reported DRMs within NS3/4A, NS5A and NS5B are not drug-induced; rather, they are already present in HCV strains, as they were also detected in HCV-naïve patients. This study highlights several hot spots in which HLA and drug selective pressure overlap. Interestingly, these overlapping mutations were frequently observed among many HCV genotypes. This study implicates that knowledge of the host HLA type and HCV subtype/genotype can provide important information in defining personalized therapy.
丙型肝炎病毒（HCV）感染期间的细胞免疫反应（T细胞反应）是决定感染结果的重要因素。HCV通过在其基因组中对HLA加工/呈递重要的特定位点诱导突变来适应宿主免疫反应。此外，HCV还适应抵抗用于限制其复制的潜在药物，如直接作用抗病毒药物（DAA）。尽管DAA显著减轻了疾病负担，但对这些药物的耐药性仍然是HCV感染治疗的一项挑战。最近，在HCV蛋白（NS3/4A、NS5A和NS5B）中观察到的耐药突变（DRM）引发了人们对耐药性出现可能会损害DAA有效性的高度关注。因此，本研究对NS3/4A、NS5A和NS5B的耐药变异进行了调查，并在来自所有HCV基因型的大量蛋白序列中检测了它们的流行情况。此外，还预测了潜在的CD4和CD8 T细胞表位，并探讨了它们与基因变异的重叠情况。研究结果表明，NS3/4A、NS5A和NS5B中许多已报道的DRM并非药物诱导产生；相反，它们已存在于HCV毒株中，因为在未感染HCV的患者中也检测到了这些变异。本研究突出了HLA和药物选择压力重叠的几个热点。有趣的是，这些重叠突变在许多HCV基因型中经常出现。本研究表明，了解宿主HLA类型和HCV亚型/基因型可为确定个性化治疗提供重要信息。
