A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses
A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses
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DOI：
10.1128/jvi.06665-11
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发表时间：
2012-03-01
影响因子：
5.4
通讯作者：
Zhou, Paul
中科院分区：
文献类型：
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作者：
Hu, Hongxing;Voss, Jarrod;Zhou, Paul
甲型流感病毒感染是对全球公共卫生的持续威胁，因为它能够通过快速的遗传漂变和转移来逃避免疫监测。目前针对甲型流感病毒的疫苗提供了对与疫苗株相似的病毒分离株的免疫力。针对保守表位的高亲和力中和抗体可以提供对不同流感病毒株的免疫力和对未来大流行病毒的保护。在这项研究中，通过使用高灵敏度的H5 N1假型为基础的中和试验，以筛选人单克隆抗体的记忆B细胞从H5 N1感染的个人和分子克隆技术，我们开发了三个完全人源性单克隆抗体。其中，抗体65 C6对除亚支7.2外的所有H5进化支和亚进化支表现出有效的中和活性，并对小鼠中的高致病性禽流感H5 N1病毒表现出预防和治疗功效。通过电子显微镜和表位作图对血凝素（HA）-抗体复合物的研究表明，抗体65 C6结合至在HA的膜远端球状结构域的尖端上的位置118、121、161、164和167（根据成熟H5编号）处包含氨基酸残基的构象表位。因此，我们得出结论，抗体65 C6识别HA球状头部中的中和表位，该中和表位在几乎所有不同的H5 N1流感毒株中是保守的。
Influenza A virus infection is a persistent threat to public health worldwide due to its ability to evade immune surveillance through rapid genetic drift and shift. Current vaccines against influenza A virus provide immunity to viral isolates that are similar to vaccine strains. High-affinity neutralizing antibodies against conserved epitopes could provide immunity to diverse influenza virus strains and protection against future pandemic viruses. In this study, by using a highly sensitive H5N1 pseudotype-based neutralization assay to screen human monoclonal antibodies produced by memory B cells from an H5N1-infected individual and molecular cloning techniques, we developed three fully human monoclonal antibodies. Among them, antibody 65C6 exhibited potent neutralization activity against all H5 clades and subclades except for subclade 7.2 and prophylactic and therapeutic efficacy against highly pathogenic avian influenza H5N1 viruses in mice. Studies on hemagglutinin (HA)-antibody complexes by electron microscopy and epitope mapping indicate that antibody 65C6 binds to a conformational epitope comprising amino acid residues at positions 118, 121, 161, 164, and 167 (according to mature H5 numbering) on the tip of the membrane-distal globular domain of HA. Thus, we conclude that antibody 65C6 recognizes a neutralization epitope in the globular head of HA that is conserved among almost all divergent H5N1 influenza stains.