A Broadly Reactive Human Anti-hemagglutinin Stem Monoclonal Antibody That Inhibits Influenza A Virus Particle Release.
A Broadly Reactive Human Anti-hemagglutinin Stem Monoclonal Antibody That Inhibits Influenza A Virus Particle Release.
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DOI：
10.1016/j.ebiom.2017.03.007
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发表时间：
2017-03
期刊：
影响因子：
11.1
通讯作者：
Kawaoka Y
中科院分区：
文献类型：
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作者：
Yamayoshi S;Uraki R;Ito M;Kiso M;Nakatsu S;Yasuhara A;Oishi K;Sasaki T;Ikuta K;Kawaoka Y
针对甲型流感病毒的血凝素（HA）茎的许多广泛反应性人单克隆抗体已被开发用于治疗应用。这些抗体通常抑制病毒进入步骤，特别是膜融合所需的HA构象变化。为了更好地理解这些抗体抑制病毒复制的机制，我们建立了广泛反应的人抗HA干抗体，并通过检查它们与18种HA亚型的反应性，评估它们的体内保护功效，鉴定它们的表位，并表征它们的抑制机制来确定这些抗体的性质。在我们产生的8种人单克隆抗体中，其识别至少3种测试的可溶性HA抗原亚型，克隆S9-1-10/5-1与18种HA亚型反应，并保护小鼠免受H1N1 pdm 09、H3 N2、H5 N1和H7N9病毒的致死性感染。该抗体识别HA茎中的HA 2螺旋A，并抑制病毒颗粒从感染细胞释放，但不完全阻断病毒进入。这些结果表明，广泛反应性的人抗HA干细胞抗体可通过抑制病毒颗粒释放而表现出保护功效。这些发现扩展了我们对广泛反应性干细胞靶向抗体抑制病毒复制的机制的了解，并为通用疫苗开发提供了有价值的信息。分离出一种广泛的小鼠保护性抗HA干抗体S9-1-10/5-1。S9-1-10/5-1主要抑制病毒释放而不是病毒进入。S9-1-10/5-1通过在相邻病毒粒子之间交联HA分子来束缚病毒粒子。针对流感HA茎的广泛反应性人单克隆抗体由于其针对多种HA亚型的潜在效用而受到关注。这些抗体中的一些通过抗体依赖性细胞毒性抑制病毒进入和/或保护小鼠。在这里，我们确定了一种人单克隆抗体，抑制病毒繁殖，在体外和体内，主要是抑制病毒颗粒的释放。这一发现提供了抗HA茎抗体的另一种抑制作用机制，表明抗HA茎抗体由于其多能性而可能是有效的抗病毒药物。
Many broadly reactive human monoclonal antibodies against the hemagglutinin (HA) stem of influenza A virus have been developed for therapeutic applications. These antibodies typically inhibit viral entry steps, especially the HA conformational change that is required for membrane fusion. To better understand the mechanisms by which such antibodies inhibit viral replication, we established broadly reactive human anti-HA stem antibodies and determined the properties of these antibodies by examining their reactivity with 18 subtypes of HA, evaluating their in vivo protective efficacy, identifying their epitopes, and characterizing their inhibitory mechanisms. Among the eight human monoclonal antibodies we generated, which recognized at least 3 subtypes of the soluble HA antigens tested, clone S9-1-10/5-1 reacted with 18 subtypes of HA and protected mice from lethal infection with H1N1pdm09, H3N2, H5N1, and H7N9 viruses. This antibody recognized the HA2 helix A in the HA stem, and inhibited virus particle release from infected cells but did not block viral entry completely. These results show that broadly reactive human anti-HA stem antibodies can exhibit protective efficacy by inhibiting virus particle release. These findings expand our knowledge of the mechanisms by which broadly reactive stem-targeting antibodies inhibit viral replication and provide valuable information for universal vaccine development. A broadly mouse-protective anti-HA stem antibody, S9-1-10/5-1, was isolated. S9-1-10/5-1 mainly inhibited virus release rather than virus entry. S9-1-10/5-1 tethers virions via crosslinking HA molecules between neighboring virions. Broadly reactive human monoclonal antibodies against the influenza HA stem have received attention because of their potential utility against multiple HA subtypes. Some of these antibodies inhibit virus entry and/or protect mice via antibody-dependent cellular cytotoxicity. Here, we identified a human monoclonal antibody that suppresses virus propagation in vitro and in vivo by primarily inhibiting virus particle release. This finding provides another inhibitory mechanism of action for the anti-HA stem antibodies, indicating that the anti-HA stem antibodies could be potent anti-virals due to their pluripotency.