CD8(+) T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress.
CD8(+) T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress.
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CD8( ) T 细胞反应相关乙型肝炎病毒核心蛋白的进化和疾病进展。
DOI：
10.1128/jvi.02120-17
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发表时间：
2018
影响因子：
5.4
通讯作者：
Meng Songdong
中科院分区：
文献类型：
--
作者：
Zhang Yu;Wu Yan;Deng Mengmeng;Xu Dongping;Li Xiaodong;Xu Zhihui;Hu Jun;Zhang Han;Liu Kefang;Zhao Yingze;Gao Feng;Bi Shengli;Gao George F;Zhao Jingmin;Liu William J;Meng Songdong
在细胞毒性T细胞（CTL）的免疫压力下，B型肝炎病毒（HBV）进化为更可能在表位内积累突变以逃避免疫检测。然而，关于免疫压力相关的HBV T细胞表位突变的特定模式及其与疾病进展的联系知之甚少。在这里，我们观察到HBV核心蛋白（HBc）的累积变异与HBV感染的疾病严重程度的相关性。进一步的分析表明这些替换主要位于HBc蛋白的CD 8 + T细胞表位内，这些替换在我们的研究中以无偏倚的方式进行了系统的筛选和鉴定。从单个肽水平到人类白细胞抗原I（HLA-I）限制性群体水平，我们阐明了这些定义明确的HLA-I限制性T细胞表位的突变显着降低抗病毒活性特异性CTL，并与HBV感染患者的临床参数和疾病进展呈正相关。基于105个HBV病毒基因组测序的病毒表位变异的分子模式表明，C-末端部分（Pc），尤其是Pc-1和Pc-2位置，具有最高的突变率。对与不同的CD 8 + T细胞表位复合的HLA-A*02的进一步结构分析显示，M形HBc衍生表位的高度可变的C端凸起峰暴露于溶剂，并且T细胞受体的大多数CDR 3 β在其上盘旋。这些数据揭示了T细胞免疫相关的病毒进化的分子和免疫学机制的B型肝炎的进展，这是有益的设计免疫疗法和vaccine.IMPORTANCEThe特定模式的T细胞表位的序列多态性和HBV表位突变相关的疾病进展的免疫机制在很大程度上是不清楚的。在这项研究中，我们系统地评估了CD 8 +T细胞对HBV疾病进展相关演变的贡献。通过基于肽库对患者T细胞应答的评估，我们从单表位水平到整体HLA-I限制性肽水平，全面表征了慢性B型肝炎临床参数与病毒抗病毒T细胞应答相关突变的相关性。此外，我们研究了HLA-A2限制性肽免疫逃逸的分子基础，发现抗原表位的暴露于溶剂的C末端部分在CDR 3 β识别下高度可变。我们的工作可能提供一个全面的评价病毒突变的影响宿主CTL反应在HBV疾病进展的背景下的全部剧目的HBc衍生表位。
Under the immune pressure of cytotoxic T cells (CTLs), hepatitis B virus (HBV) evolves to accumulate mutations more likely within epitopes to evade immune detection. However, little is known about the specific patterns of the immune pressure-associated HBV mutation of T-cell epitopes and their link to disease progression. Here, we observed a correlation of the accumulated variants on HBV core protein (HBc) with the disease severity of HBV infection. Further analysis indicated that these substitutions were mostly located within CD8+T-cell epitopes of HBc protein, which were systematically screened and identified in an unbiased manner in our study. From individual peptide level to the human leukocyte antigen I (HLA-I)-restricted population level, we elucidated that the mutations in these well-defined HLA-I-restricted T-cell epitopes significantly decreased antiviral activity-specific CTLs and were positively associated with clinical parameters and disease progression in HBV-infected patients. The molecular pattern for viral epitope variations based on the sequencing of 105 HBV virus genomes indicated that the C-terminal portion (Pc), especially the Pc-1 and Pc-2 positions, have the highest mutation rates. Further structural analysis of HLA-A*02 complexed to diverse CD8+T-cell epitopes revealed that the highly variable C-terminal bulged peak of M-shaped HBc-derived epitopes are solvent exposed, and most of the CDR3βs of the T-cell receptor hover over them. These data shed light on the molecular and immunological mechanisms of T-cell immunity-associated viral evolution in hepatitis B progression, which is beneficial for designing immunotherapies and vaccines.IMPORTANCEThe specific patterns of sequence polymorphisms of T-cell epitopes and the immune mechanisms of the HBV epitope mutation-linked disease progression are largely unclear. In this study, we systematically evaluated the contribution of CD8+T cells to the disease progress-associated evolution of HBV. By evaluation of patient T-cell responses based on the peptide repertoire, we comprehensively characterized the association of clinical parameters in chronic hepatitis B with the antiviral T-cell response-associated mutations of the viruses from the single-epitope level to the overall HLA-I-restricted peptide levels. Furthermore, we investigated the molecular basis of the HLA-A2-restricted peptide immune escape and found that the solvent-exposed C-terminal portion of the epitopes is highly variable under CDR3β recognition. Our work may provide a comprehensive evaluation of viral mutations impacted by the host CTL response in HBV disease progression in the context of the full repertoire of HBc-derived epitopes.