Junctional and somatic hypermutation-induced CX4C motif is critical for the recognition of a highly conserved epitope on HCV E2 by a human broadly neutralizing antibody  

作　　者：Chunyan Yi Jing Xia Lan He Zhiyang Ling Xuesong Wang Yu Yan Jiangjun Wang Xinhao Zhao Weiguo Fan Xiaoyu Sun Ronghua Zhang Sheng Ye Rongguang Zhang Yongfen Xu Liyan Ma Yaguang Zhang Honglin Zhou Zhong Huang Junqi Niu Gang Long Junxia Lu Jin Zhong Bing Sun 

机构地区：[1]State Key Laboratory of Cell Biology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences/University of Chinese Academy of Sciences,Shanghai,China [2]CAS Key Laboratory of Molecular Virology and Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences/University of Chinese Academy of Sciences,Shanghai,China [3]School of Life Science and Technology,ShanghaiTech University,Shanghai,China [4]CAS Key Laboratory of Synthetic Chemistry of Natural Substances,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai,China [5]College of Biology,Hunan Provincial Key Laboratory of Medical Virology,Hunan University,Changsha,China [6]National Laboratory of Biophysics,Institute of Biophysics,Chinese Academy of Sciences/University of Chinese Academy of Sciences Bdjing,Beijing,China [7]Interdisciplinary Innovation Institute of Medicine&Engineering,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,School of Biological Science and Medical Engineering,Beihang University,Beijing,China [8]Nanjing Galaxy Biopharma Co.,Ltd,Nanjing,China [9]Hepatology Section,First Hospital,University of Jilin,Changchun,China

出　　处：《Cellular & Molecular Immunology》2021年第3期675-685,共11页中国免疫学杂志（英文版）

基　　金：supported by grants from the Chinese National 973 Program(2015CB554302);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19000000)to B.S.;the Chinese National 973 Program(2015CB554300);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29010205)to M.;the National Natural Science Foundation of China(31670172);Shanghai Science and Technology Innovation Action(16DZ1910100)to B.S.;Nanjing Galaxy Biopharma C.O.

摘　　要：Induction of broadly neutralizing monoclonal antibodies(bNAbs)that bind to the viral envelope glycoproteins is a major goal of hepatitis C virus(HCV)vaccine research.The study of bNAbs arising in natural infection is essential in this endeavor.We generated a human antibody,8D6,recognizing the E2 protein of HCV isolated from a chronic hepatitis C patient.This antibody shows broadly neutralizing activity,which covers a pan-genotypic panel of cell culture-derived HCV virions(HCVcc).Functional and epitope analyses demonstrated that 8D6 can block the interaction between E2 and CD81 by targeting a highly conserved epitope on E2.We describe how the 8D6 lineage evolved via somatic hypermutation to achieve broad neutralization.We found that the V(D)J recombination-generated junctional and somatic hypermutation-induced disulfide bridge(C-C)motif in the CDRH3 is critical for the broad neutralization and binding activity of 8D6.This motif is conserved among a series of broadly neutralizing HCV antibodies,indicating a common binding model.Next,the 8D6 inferred germline(iGL)was reconstructed and tested for its binding affinity and neutralization activity.Interestingly,8D6 iGL-mediated relatively strong inhibition of the 1b genotype PR79L9 strain,suggesting that PR79L9 may serve as a potential natural viral strain that provides E2 sequences that induce bNAbs.Overall,our detailed epitope mapping and genetic studies of the HCV E2-specific mAb 8D6 have allowed for further refinement of antigenic sites on E2 and reveal a new mechanism to generate a functional CDRH3,while its iGL can serve as a probe to identify potential HCV vaccine strains.

关 键 词：Hepatitis C virus neutralizing antibody inferred germline CDRH3 disulfide bridge motif 

分 类 号：R392[医药卫生—免疫学]