Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses
Conserved Neutralizing Epitope at Globular Head of Hemagglutinin in H3N2 Influenza Viruses
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DOI：
10.1128/jvi.00420-14
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发表时间：
2014-07-01
影响因子：
5.4
通讯作者：
Yokoyama, Shigeyuki
中科院分区：
文献类型：
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作者：
Iba, Yoshitaka;Fujii, Yoshifumi;Yokoyama, Shigeyuki
靶向流感病毒血凝素的中和抗体抑制血凝素与细胞受体的结合或防止膜融合所需的低pH诱导的血凝素构象变化。通常，前一种类型的抗体结合由HA 1形成的球状头部，具有窄的菌株特异性，而后一种类型的抗体结合主要由HA 2形成的茎部，具有宽的菌株特异性。在本研究中，我们分析了抗H3 N2病毒F005-126的广泛中和人抗体的表位和功能。与血凝素复合的F005-126 Fab的晶体结构显示，抗体与球状头部结合，跨越血凝素三聚体中两个血凝素单体形成的裂缝，并将它们交联。它识别两个肽部分（位点L和R）和一个使用重链中的三个互补决定区和框架3在残基285处与天冬酰胺连接的聚糖。抗体与位点L（残基171至173、239和240）和R（残基91、92、270至273、284和285）的结合主要通过与这些位点中肽的主链的货车德瓦尔斯接触介导，其次通过与HA 1中保守序列的少数侧链的氢键介导。此外，F005-126识别的聚糖在H3 N2病毒中是保守的。F005-126具有防止低pH诱导的血凝素构象变化的能力。新鉴定的保守表位（包括聚糖）在人体中应具有免疫原性，并可诱导产生针对H3病毒的广泛中和抗体。
Neutralizing antibodies that target the hemagglutinin of influenza virus either inhibit binding of hemagglutinin to cellular receptors or prevent the low-pH-induced conformational change in hemagglutinin required for membrane fusion. In general, the former type of antibody binds to the globular head formed by HA1 and has narrow strain specificity, while the latter type binds to the stem mainly formed by HA2 and has broad strain specificity. In the present study, we analyzed the epitope and function of a broadly neutralizing human antibody against H3N2 viruses, F005-126. The crystal structure of F005-126 Fab in complex with hemagglutinin revealed that the antibody binds to the globular head, spans a cleft formed by two hemagglutinin monomers in a hemagglutinin trimer, and cross-links them. It recognizes two peptide portions (sites L and R) and a glycan linked to asparagine at residue 285 using three complementarity-determining regions and framework 3 in the heavy chain. Binding of the antibody to sites L (residues 171 to 173, 239, and 240) and R (residues 91, 92, 270 to 273, 284, and 285) is mediated mainly by van der Waals contacts with the main chains of the peptides in these sites and secondarily by hydrogen bonds with a few side chains of conserved sequences in HA1. Furthermore, the glycan recognized by F005-126 is conserved among H3N2 viruses. F005-126 has the ability to prevent low-pH-induced conformational changes in hemagglutinin. The newly identified conserved epitope, including the glycan, should be immunogenic in humans and may induce production of broadly neutralizing antibodies against H3 viruses.