PDF(Pubmed)
Abstract：
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
摘要：
丙型肝炎病毒（HCV）的非结构蛋白区域的突变是慢性肝炎对直接作用抗病毒药物（DAA）治疗的非持续病毒学应答（SVR）的原因;然而，有没有这些突变的非SVR病例。在这项研究中,我们检测了ombitasvir/paritaprevir/ritonavir治疗前后外周血的免疫细胞谱,并筛选了可用于预测DAA治疗效果的基因.荧光激活细胞分选分析表明，程序性细胞死亡-1阳性（PD-1+）效应调节性T细胞（eTregs）的中位频率，PD-1+CD8+T细胞,PD-1+辅助T细胞在SVR病例中显著减少，但在非SVR病例中没有显著变化。在治疗前后，SVR组的PD-1+初始Tregs的频率明显高于非SVR组。在接受其他DAA治疗的患者中发现了类似的结果(例如，daclatasvir加asunaprevir），并支持HCV治疗后的免疫反应。RNA测序分析表明，SVR组中与免疫反应相关的基因表达显着增加，而与细胞内和细胞外信号转导相关的基因在非SVR组中高表达。因此,我们搜索了与PD-1+eTregs和CD8+T细胞相关的基因,这些基因在SVR组和非SVR组之间存在显著差异,发现T-box转录因子21与非SVR状态相关.这些结果表明,与突变相关的药物抗性分开的DAA治疗后,PD-1相关的信号传导途径与非SVR机制相关。
