Junctional and somatic hypermutation-induced CX4C motif is critical for the recognition of a highly conserved epitope on HCV E2 by a human broadly neutralizing antibody.,Cellular & Molecular Immunology

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Junctional and somatic hypermutation-induced CX4C motif is critical for the recognition of a highly conserved epitope on HCV E2 by a human broadly neutralizing antibody.
Cellular & Molecular Immunology ( IF 21.8 ) Pub Date : 2020-03-31 , DOI: 10.1038/s41423-020-0403-1
Chunyan Yi ₁ , Jing Xia ₂ , Lan He _{3,

4,

5} , Zhiyang Ling ₁ , Xuesong Wang ₂ , Yu Yan ₂ , Jiangjun Wang ₁ , Xinhao Zhao ₂ , Weiguo Fan ₂ , Xiaoyu Sun ₁ , Ronghua Zhang ₁ , Sheng Ye _{6,

7} , Rongguang Zhang ₆ , Yongfen Xu ₂ , Liyan Ma ₁ , Yaguang Zhang ₁ , Honglin Zhou ₈ , Zhong Huang ₂ , Junqi Niu ₉ , Gang Long ₂ , Junxia Lu ₃ , Jin Zhong ₂ , Bing Sun ₁

Affiliation

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
College of Biology, Hunan Provincial Key Laboratory of Medical Virology, Hunan University, Changsha, China.
National Laboratory of Biophysics, Institute of Biophysics, Chinese Academy of Sciences; University of Chinese Academy of Sciences Beijing, Beijing, China.
Interdisciplinary Innovation Institute of Medicine & Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
Nanjing Galaxy Biopharma Co., Ltd, Nanjing, China.
Hepatology Section, First Hospital, University of Jilin, Changchun, China.

Induction of broadly neutralizing monoclonal antibodies (bNAbs) that bind to the viral envelope glycoproteins is a major goal of hepatitis C virus (HCV) vaccine research. The study of bNAbs arising in natural infection is essential in this endeavor. We generated a human antibody, 8D6, recognizing the E2 protein of HCV isolated from a chronic hepatitis C patient. This antibody shows broadly neutralizing activity, which covers a pan-genotypic panel of cell culture-derived HCV virions (HCVcc). Functional and epitope analyses demonstrated that 8D6 can block the interaction between E2 and CD81 by targeting a highly conserved epitope on E2. We describe how the 8D6 lineage evolved via somatic hypermutation to achieve broad neutralization. We found that the V(D)J recombination-generated junctional and somatic hypermutation-induced disulfide bridge (C-C) motif in the CDRH3 is critical for the broad neutralization and binding activity of 8D6. This motif is conserved among a series of broadly neutralizing HCV antibodies, indicating a common binding model. Next, the 8D6 inferred germline (iGL) was reconstructed and tested for its binding affinity and neutralization activity. Interestingly, 8D6 iGL-mediated relatively strong inhibition of the 1b genotype PR79L9 strain, suggesting that PR79L9 may serve as a potential natural viral strain that provides E2 sequences that induce bNAbs. Overall, our detailed epitope mapping and genetic studies of the HCV E2-specific mAb 8D6 have allowed for further refinement of antigenic sites on E2 and reveal a new mechanism to generate a functional CDRH3, while its iGL can serve as a probe to identify potential HCV vaccine strains.

中文翻译：

连接和体细胞超突变诱导的 CX4C 基序对于人类广泛中和抗体识别 HCV E2 上高度保守的表位至关重要。

与病毒包膜糖蛋白结合的广泛中和单克隆抗体 (bNAb) 的诱导是丙型肝炎病毒 (HCV) 疫苗研究的主要目标。对自然感染中产生的 bNAb 的研究在这一努力中至关重要。我们生成了一种人类抗体 8D6，可识别从一名慢性丙型肝炎患者身上分离的 HCV 的 E2 蛋白。该抗体显示出广泛的中和活性，涵盖了细胞培养衍生的 HCV 病毒粒子 (HCVcc) 的泛基因型面板。功能和表位分析表明，8D6 可以通过靶向 E2 上高度保守的表位来阻断 E2 和 CD81 之间的相互作用。我们描述了 8D6 谱系如何通过体细胞超突变进化以实现广泛的中和。我们发现 CDRH3 中 V(D)J 重组产生的连接和体细胞超突变诱导的二硫键 (CC) 基序对于 8D6 的广泛中和和结合活性至关重要。该基序在一系列广泛中和的 HCV 抗体中是保守的，表明具有共同的结合模型。接下来，8D6 推断种系 (iGL) 被重建并测试其结合亲和力和中和活性。有趣的是，8D6 iGL 介导了对 1b 基因型 PR79L9 菌株的相对较强的抑制，这表明 PR79L9 可能作为一种潜在的天然病毒菌株，提供可诱导 bNAb 的 E2 序列。总体而言，我们对 HCV E2 特异性 mAb 8D6 的详细表位作图和遗传研究允许进一步改进 E2 上的抗原位点，并揭示产生功能性 CDRH3 的新机制，

更新日期：2020-04-24

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