An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein
An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein
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DOI：
10.7554/elife.53169
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发表时间：
2020-03-03
期刊：
影响因子：
7.7
通讯作者：
Bjorkman, Pamela J.
中科院分区：
文献类型：
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作者：
Flyak, Andrew, I;Ruiz, Stormy E.;Bjorkman, Pamela J.
控制丙型肝炎病毒（HCV）的流行需要一种能预防多种HCV变异株的疫苗。从HCV感染者体内分离出的针对前层的广谱中和抗体（bNAb）与E2复合物的结构显示，含有二硫键的互补决定区3（CDRH3）呈现直形（感染清除者）或弯曲形（慢性感染者）构象。为了研究含有直形与弯曲形二硫键的CDRH3是否对特定的HCV感染者具有特异性，我们解析了HCV E2胞外域与AR3X形成的复合物的晶体结构，AR3X是一种具有异常长的CDRH2的bNAb，它是从产生弯曲CDRH3 bNAb的慢性感染者体内分离出来的。该结构显示AR3X利用其超长的CDRH2和一个含有二硫键基序的直形CDRH3来识别E2前层。这些结果表明，在单个个体中可以诱导出直形和弯曲形CDRH3这两类HCV bNAb，揭示了VH1 - 69衍生的bNAb的结构可塑性。
A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.