一类 HCV 广谱中和抗体及其前体的免疫遗传学和结构分析。
Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors.
机构信息
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
出版信息
Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):7569-7574. doi: 10.1073/pnas.1802378115. Epub 2018 Jun 28.
Abstract
Elicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. Six of the mAbs recognize the conserved E2 antigenic site 412-423 (AS412) and cross-neutralize diverse HCV genotypes. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Intriguingly, the anti-HCV activity of one antibody lineage is associated with maturation of the light chain (LC), whereas the other lineage is dependent on heavy-chain (HC) maturation. Crystal structures of GL precursors of the LC-dependent lineage in complex with AS412 offer critical insights into the maturation process of bnAbs to HCV, providing a scientific foundation for utilizing the mouse model to study AS412-targeting vaccine candidates.
摘要
诱导广谱中和抗体 (bnAbs) 是针对具有不同抗原性的病原体进行合理疫苗设计的主要策略。在这里，我们研究了一组用丙型肝炎病毒 (HCV) 包膜糖蛋白 E1E2 免疫的小鼠产生的单克隆抗体 (mAb)。其中 6 种 mAb 识别保守的 E2 抗原表位 412-423 (AS412)，并交叉中和多种 HCV 基因型。免疫遗传和结构分析表明，这些抗体来源于两个不同的胚系 (GL) 前体，并以 β 发夹构象结合 AS412。有趣的是，一种抗体谱系的抗 HCV 活性与轻链 (LC) 的成熟有关，而另一种谱系则依赖于重链 (HC) 的成熟。与 AS412 结合的 LC 依赖性谱系 GL 前体的晶体结构提供了对 HCV bnAbs 成熟过程的重要见解，为利用小鼠模型研究 AS412 靶向疫苗候选物提供了科学基础。
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