干扰素-α (IFN-α) 是用于治疗丙型肝炎病毒 (HCV) 感染的抗病毒免疫反应的关键介质。尽管临床上有效，但 IFN-α 经常会诱发功能性情绪和动机受损症状，特别是疲劳。与通常在治疗数周后出现的情绪障碍不同，疲劳往往会迅速出现并发展，通常在第一次注射 IFN-α 后数小时内出现。尽管疲劳是 IFN-α 和其他免疫疗法期间功能损伤的主要来源，但人们对疲劳背后的生物学机制仍然知之甚少。在这里，我们的目的是确定对 IFN-α 的急性免疫反应特征，以预测疲劳的后期发展。在这项探索性研究中，我们分析了 27 名开始 IFN-α 和利巴韦林治疗的 HCV 患者的纵向样本的全血转录组学。在基线和首次 IFN-α 剂量后 4.5 小时采集血样，并使用 Affymetrix Human Gene 1.1 ST Array Strips 获得转录组数据。使用 Partek Genomics Suite V6.6 评估基因表达数据可视化和质量控制，并使用 STRING 和 Ingenuity Pathway Analysis (IPA) 评估蛋白质-蛋白质相互作用网络。使用疲劳视觉模拟量表 (fVAS) 记录基线、治疗开始后 4.5 小时和 4 周的疲劳症状。IFN-α 与 526 个转录物的上调和 228 个基因的下调相关，表明快速的转录组反应注射后 4.5 小时内全血中。 93 个基因与疲劳变化显着正相关，从基线到 4.5 小时测量基因表达变化，并通过 fVAS 评估从基线到第 4 周疲劳增加。我们发现了一个主要由胞质核糖体单元和泛素蛋白组成的新网络，该网络与调节 mTOR 信号传导有关，该信号与开始 IFN-α 治疗后 4 周出现疲劳有关（p=0.0078）。我们的研究结果表明，这种合成代谢的急性激活IFN-α 的分解代谢网络可能会导致疲劳体验，类似于癌症相关疲劳中发现的证据。有必要进行进一步调查以确认这些观察结果的探索性质。版权所有 © 2024。由 Elsevier Inc. 出版。

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis-C virus (HCV) infection. Though clinically effective, IFN-α frequently induces functionally impairing mood and motivation symptoms, particularly fatigue. Unlike mood impairment, which typically emerges after weeks of treatment, fatigue tends to emerge and evolve rapidly, typically within hours of the first IFN-α injection. Despite being a major source of functional impairment during IFN-α and other immune-based therapies, the biological mechanisms underlying fatigue remain poorly understood. Here, we aimed to identify acute immune-response signatures to IFN-α that could predict the later development of fatigue.In this exploratory study, we analyzed whole blood transcriptomics in a longitudinal sample of 27 HCV patients initiating IFN-α and Ribavirin therapy. Blood samples were obtained at baseline and 4½ hours after the first IFN-α dose and transcriptomic data was obtained using Affymetrix Human Gene 1.1 ST Array Strips. Gene expression data visualization and quality control were assessed using Partek Genomics Suite V6.6 and protein-protein interaction networks using STRING and Ingenuity Pathway Analysis (IPA). A Fatigue Visual Analogue Scale (fVAS) was utilized to record fatigue symptoms at baseline, 4½ hours and 4 weeks after initiation of treatment.IFN-α was associated with an upregulation of 526 transcripts and a downregulation of 228 genes, indicating a rapid transcriptomic response in whole blood within 4½ hours of injection. 93 genes were significantly positively correlated with changes in fatigue, with gene expression changes measured from baseline to 4.5 h and increases in fatigue assessed from baseline to week 4 on the fVAS. We identified a novel network of predominantly cytosolic ribosomal units and ubiquitin proteins implicated in modulating mTOR signaling that was associated with the development of fatigue 4 weeks after initiation of IFN-α treatment (p = 0.0078).Our findings suggest that acute activation of this anabolic/catabolic network by IFN-α may predispose to the experience of fatigue similar to evidence found in cancer-related fatigue. Further investigation is warranted to confirm the exploratory nature of these observations.Copyright © 2024. Published by Elsevier Inc.