Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance
Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance
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DOI：
10.1172/jci.insight.92872
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发表时间：
2017-05-04
期刊：
影响因子：
8
通讯作者：
Crowe, James E., Jr.
中科院分区：
文献类型：
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作者：
Bailey, Justin R.;Flyak, Andrew I.;Crowe, James E., Jr.
在这里，我们报告的广泛中和单克隆抗体（bNAbs）的人与广泛中和血清自发清除丙型肝炎病毒（HCV）感染的分离。我们发现来自两个供体的bNAb结合相同的表位，并且由相同的种系重链可变基因片段编码。值得注意的是，这些bNAb由具有稀疏体细胞突变的抗体可变基因编码。对于最有效的bNAb之一，这些体细胞突变对于抗体中和宽度和与感染后期循环的自体包膜变体的结合至关重要。然而，体细胞突变对于bNAb未突变的祖先与早期自体传播/创始者病毒的包膜蛋白的结合是不必要的。本研究鉴定了一种有利于早期识别HCV保守表位的公共B细胞克隆型，证明了抗HCV bNAb可以在相对较少的体细胞突变的情况下实现实质性中和宽度，并鉴定了有利于抗HCV bNAb B在体内选择和成熟的HCV包膜变体。这些数据提供了深入了解免疫介导的清除HCV感染的分子机制，并提出了一个路线图，以指导开发一种疫苗，能够刺激抗HCV bNAb与生理数量的体细胞突变的疫苗反应的特点。
Here, we report the isolation of broadly neutralizing mAbs (bNAbs) from persons with broadly neutralizing serum who spontaneously cleared hepatitis C virus (HCV) infection. We found that bNAbs from two donors bound the same epitope and were encoded by the same germline heavy chain variable gene segment. Remarkably, these bNAbs were encoded by antibody variable genes with sparse somatic mutations. For one of the most potent bNAbs, these somatic mutations were critical for antibody neutralizing breadth and for binding to autologous envelope variants circulating late in infection. However, somatic mutations were not necessary for binding of the bNAb unmutated ancestor to envelope proteins of early autologous transmitted/ founder viruses. This study identifies a public B cell clonotype favoring early recognition of a conserved HCV epitope, proving that anti-HCV bNAbs can achieve substantial neutralizing breadth with relatively few somatic mutations, and identifies HCV envelope variants that favored selection and maturation of an anti-HCV bNAb in vivo. These data provide insight into the molecular mechanisms of immune-mediated clearance of HCV infection and present a roadmap to guide development of a vaccine capable of stimulating anti-HCV bNAbs with a physiologic number of somatic mutations characteristic of vaccine responses.