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.

Abstract

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.

• Authors: 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
• Journal: Cellular & molecular immunology (Cell Mol Immunol) Vol. 18 Issue 3 Pg. 675-685 (03 2021) ISSN: 2042-0226 [Electronic] China
• PMID: 32235917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Broadly Neutralizing Antibodies
• Complementarity Determining Regions
• Epitopes
• Hepatitis C Antibodies
• Immunoglobulin Heavy Chains
• Viral Envelope Proteins
• glycoprotein E2, Hepatitis C virus

Topics

• Antibodies, Monoclonal (pharmacology)
• Broadly Neutralizing Antibodies (pharmacology)
• Complementarity Determining Regions (genetics, immunology)
• Epitope Mapping
• Epitopes (immunology)
• Hepacivirus (immunology)
• Hepatitis C (genetics, immunology, prevention & control, virology)
• Hepatitis C Antibodies (immunology)
• Humans
• Immunoglobulin Heavy Chains
• Mutation
• Protein Interaction Domains and Motifs
• Viral Envelope Proteins (immunology)