CD8 + T细胞反应相关的乙型肝炎病毒核心蛋白和疾病进展的演

StephenW

CD8+ T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress
Yu Zhang, Yan Wu, Mengmeng Deng, Dongping Xu, Xiaodong Li, Zhihui Xu, Jun Hu, Han Zhang, Kefang Liu, Yingze Zhao, Feng Gao, Shengli Bi, George F. Gao, Jingmin Zhao, William J. Liu, Songdong Meng
J.-H. James Ou, Editor
DOI: 10.1128/JVI.02120-17

    ABSTRACT

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.

IMPORTANCE The 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.

StephenW

CD8 + T细胞反应相关的乙型肝炎病毒核心蛋白和疾病进展的演变
张宇，吴艳，邓梦萌，徐东平，李晓东，徐志辉，胡俊，张晗，刘克芳，赵迎泽，高峰，毕胜利，高乔文，赵敬民，刘威廉，宋东萌
J.-H. James Ou，编辑
DOI：10.1128 / JVI.02120-17

    抽象

在细胞毒性T细胞（CTL）的免疫压力下，乙型肝炎病毒（HBV）进化为在表位内更容易积累突变以逃避免疫检测。然而，关于T细胞表位的免疫压力相关HBV突变的特定模式及其与疾病进展的关联知之甚少。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，这些取代大多位于HBc蛋白的CD8 + T细胞表位内，在我们的研究中以无偏的方式系统地筛选和鉴定。从个体肽水平到人类白细胞抗原I（HLA-I）限制性群体水平，我们阐明这些明确定义的HLA-I限制性T细胞表位中的突变显着降低了抗病毒活性特异性CTL并且呈正相关具有临床参数和HBV感染患者的疾病进展。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。对多种CD8 + T细胞表位复合的HLA-A * 02的进一步结构分析显示，M型HBc衍生表位的高度可变的C末端凸起峰是溶剂暴露的，并且T细胞受体的大多数CDR3βs将鼠标悬停在他们身上这些数据揭示了乙型肝炎进展中T细胞免疫相关病毒进化的分子和免疫机制，这有利于设计免疫疗法和疫苗。

重要性T细胞表位序列多态性的特定模式和HBV表位突变相关疾病进展的免疫机制尚不清楚。在这项研究中，我们系统地评估了CD8 + T细胞对HBV疾病进展相关进化的贡献。通过评估基于肽库的患者T细胞反应，我们综合表征了慢性乙型肝炎临床参数与病毒从单一表位水平到整体HLA的病毒T细胞反应相关突变的关联。 I限制肽水平。此外，我们研究了HLA-A2限制性肽免疫逃逸的分子基础，并发现表位的溶剂暴露的C-末端部分在CDR3β识别下是高度可变的。我们的工作可以提供对HBc疾病进展的完整库中HBV疾病进展中宿主CTL应答影响的病毒突变的综合评估。

StephenW

https://jvi.asm.org/content/92/17/e02120-17.full

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