Bailey Justin R, Flyak Andrew I, Cohen Valerie J, Li Hui, Wasilewski Lisa N, Snider Anna E, Wang Shuyi, Learn Gerald H, Kose Nurgun, Loerinc Leah, Lampley Rebecca, Cox Andrea L, Pfaff Jennifer M, Doranz Benjamin J, Shaw George M, Ray Stuart C, Crowe James E
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
JCI Insight. 2017 May 4;2(9). doi: 10.1172/jci.insight.92872.
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.
在此,我们报告了从自发清除丙型肝炎病毒(HCV)感染的具有广泛中和血清的个体中分离出广泛中和单克隆抗体(bNAbs)。我们发现,来自两名供体的bNAbs结合相同的表位,并由相同的种系重链可变基因片段编码。值得注意的是,这些bNAbs由体细胞突变稀少的抗体可变基因编码。对于其中一种最有效的bNAbs,这些体细胞突变对于抗体中和广度以及与感染后期循环的自体包膜变体的结合至关重要。然而,体细胞突变对于未突变的bNAb祖先与早期自体传播/奠基病毒的包膜蛋白的结合并非必需。本研究鉴定出一种有利于早期识别保守HCV表位的公共B细胞克隆型,证明抗HCV bNAbs能够通过相对较少的体细胞突变实现显著的中和广度,并鉴定出有利于体内抗HCV bNAb选择和成熟的HCV包膜变体。这些数据为免疫介导清除HCV感染的分子机制提供了见解,并为指导开发能够刺激具有疫苗应答特征的生理数量体细胞突变的抗HCV bNAbs的疫苗提供了路线图。