Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains

Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The “breathing” of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.季节性流感病毒感染可造成严重的发病与死亡病例，但新型大流行性流感毒株出现带来的威胁，或许会引发更为毁灭性的后果。鉴于此，相关领域对靶向病毒表面糖蛋白血凝素（hemagglutinin, HA）的强效中和抗体的分离与表征抱有极高的研究热情。本研究利用冷冻电子显微镜（cryo-electron microscopy, cryoEM）解析了一株靶向流感H7 HA的HA头部定向单克隆抗体（monoclonal antibody, mAb）的作用机制。该抗体的表位，在迄今所有HA结构所典型呈现的紧凑融合前构象中，并不具备溶剂可及性。反之，该抗体结合于HA头部原聚体之间的表位，该表位在融合前构象中必须处于部分或瞬时暴露的状态。该表位的暴露暗示了HA原聚体存在“呼吸”动态变化，这与I类融合蛋白的亚稳态特性相符。因此，该结构很可能代表了病毒融合过程中的早期结构中间体。对保守中和表位瞬时暴露程度的解析，还有望为对抗流感开辟此前未被认知的全新途径。