Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human
Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human
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在恢复期人类中开发针对寨卡病毒的有效且具有保护性的种系样抗体谱系
DOI：
10.3389/fimmu.2019.02424
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发表时间：
2019-10-24
影响因子：
7.3
通讯作者：
Yu, Lei
中科院分区：
文献类型：
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作者：
Gao, Fei;Lin, Xiaohe;Yu, Lei
寨卡病毒（ZIKV）特异性中和抗体对于针对ZIKV感染的基于抗体的干预和疫苗设计具有很大的希望。然而，它们在感染患者中的发展仍不清楚。在此，我们应用下一代测序（NGS）来探测从ZIKV恢复期个体分离的有效且保护性的ZIKV E DIII特异性抗体ZK2B10的动态发展。无偏库分析显示抗体可变区种系基因的使用发生了巨大变化。然而，ZK2B10的谱系追踪揭示了在症状发作后的12个月期间有限的体细胞超突变和短暂扩增。NGS衍生的生殖系样ZK2B10体细胞变体有效地中和ZIKV，并保护小鼠免受ZIKV的致死性攻击，而与登革病毒（DENV）没有可检测的交叉反应性。定点突变确定了λ链内的两个残基N31和S91，这对ZK 2B10的功能成熟至关重要。这里揭示的库和谱系特征将有助于阐明针对ZIKV感染的EDIII定向抗体的发育过程和保护潜力。
Zika virus (ZIKV) specific neutralizing antibodies hold great promise for antibody-based interventions and vaccine design against ZIKV infection. However, their development in infected patients remains unclear. Here, we applied next-generation sequencing (NGS) to probe the dynamic development of a potent and protective ZIKV E DIII-specific antibody ZK2B10 isolated from a ZIKV convalescent individual. The unbiased repertoire analysis showed dramatic changes in the usage of antibody variable region germline genes. However, lineage tracing of ZK2B10 revealed limited somatic hypermutation and transient expansion during the 12 months following the onset of symptoms. The NGS-derived, germline-like ZK2B10 somatic variants neutralized ZIKV potently and protected mice from lethal challenge of ZIKV without detectable cross-reactivity with Dengue virus (DENV). Site-directed mutagenesis identified two residues within the lambda chain, N31 and S91, that are essential to the functional maturation of ZK2B10. The repertoire and lineage features unveiled here will help elucidate the developmental process and protective potential of E DIII-directed antibodies against ZIKV infection.