Department of Infectious Diseases, The First People's Hospital of Kashi Prefecture, Kashi, China.
Front Cell Infect Microbiol. 2024 Nov 7;14:1480987. doi: 10.3389/fcimb.2024.1480987. eCollection 2024.
The hepatitis C virus (HCV) poses a major global health challenge, with its non-structural proteins being essential for viral replication and pathogenesis. Mutations in these proteins significantly contribute to drug resistance, necessitating innovative therapeutic strategies. This study aims to identify epitope-based therapeutic targets in the non-structural proteins of HCV genotype 1, employing in-depth in silico tools to counteract emerging drug resistance.
We retrieved approximately 250 sequences of each non-structural protein from the NCBI database, capturing a broad spectrum of variability and sequence alignments, variability analysis and physicochemical property analysis were conducted. We utilized the TEPITOOL server by IEDB to predict cytotoxic T lymphocyte (CTL) epitopes. Following this, we assessed the efficiency of TAP transport and proteasomal cleavage using IEDB's combined predictor tool. The epitopes were selected based on conservancy analysis, immunogenicity, allergenicity, and presence in non-glycosylated regions, ensuring high predictive scores and suitability as vaccine candidates. Epitopes were docked with the HLA-A*02:01 allele and Toll-like receptor-3 using the ClusPro server. The immune response potential of the epitopes was evaluated through immune stimulation.
The study identified 27 potential CTL epitopes from the non-structural proteins, including NS3, NS4a, NS4b, NS5a, and NS5b. Out of these, three lead epitopes demonstrated high conservation (>90%), strong binding affinities to HLA-A*02:01 and TLR-3, and robust immune response potential. These epitopes also showed favorable characteristics such as being non-allergenic and non-glycosylated.
This comprehensive analysis provides a promising foundation for developing an epitope-based vaccine targeting HCV non-structural proteins, offering a novel approach to overcoming drug resistance in HCV treatment.
丙型肝炎病毒（HCV）是一个主要的全球健康挑战，其非结构蛋白对于病毒复制和发病机制至关重要。这些蛋白质中的突变显著导致药物耐药性，需要创新的治疗策略。本研究旨在鉴定 HCV 基因型 1 的非结构蛋白中基于表位的治疗靶点，采用深入的计算工具来对抗新出现的药物耐药性。
我们从 NCBI 数据库中检索了每个非结构蛋白约 250 个序列，涵盖了广泛的变异性和序列比对。进行了变异性分析和物理化学性质分析。我们利用 IEDB 的 TEPITOOL 服务器预测细胞毒性 T 淋巴细胞（CTL）表位。在此之后，我们使用 IEDB 的组合预测工具评估 TAP 转运和蛋白酶体切割的效率。基于保守性分析、免疫原性、变应原性和在非糖基化区域的存在，选择表位，确保高预测评分和作为疫苗候选物的适宜性。使用 ClusPro 服务器将表位与 HLA-A*02:01 等位基因和 Toll 样受体-3 对接。通过免疫刺激评估表位的免疫反应潜力。
本研究从非结构蛋白中鉴定出 27 个潜在的 CTL 表位，包括 NS3、NS4a、NS4b、NS5a 和 NS5b。其中，三个先导表位具有高度保守性（>90%）、与 HLA-A*02:01 和 TLR-3 强结合亲和力以及强大的免疫反应潜力。这些表位还具有非变应原性和非糖基化等有利特征。
这项全面分析为开发针对 HCV 非结构蛋白的基于表位的疫苗提供了有希望的基础，为克服 HCV 治疗中的药物耐药性提供了一种新方法。
