Convergent antibody responses are associated with broad neutralization of hepatitis C virus

Frontiers in Immunology

Immunology

Nicole E. Skinner¹  Anuj Gupta²  Sarah Wheelan²  Kornel Schuebel²  Jennifer Meyers²  Srinivasan Yegnasubramanian²  James E. Crowe³  Kaitlyn E. Clark⁴  Clinton O. Ogega⁴  Nicole Frumento⁴  Harry Paul⁴  Justin R. Bailey⁴  Andrea L. Cox⁵  Stuart C. Ray⁵ 

[1] Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, United States;Department of Medicine, College of Medicine, The Ohio State University, Columbus, OH, United States;Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States;Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States;Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States;Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, United States;Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States;Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States;Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States;

关键词: hepatitis C virus;    B cell;    neutralizing antibody;    B cell receptor;    vaccine;   

DOI  :  10.3389/fimmu.2023.1135841

 received in 2023-01-01, accepted in 2023-03-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionEarly development of broadly neutralizing antibodies (bNAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein E2 is associated with spontaneous clearance of infection, so induction of bNAbs is a major goal of HCV vaccine development. However, the molecular antibody features important for broad neutralization are not known.MethodsTo identify B cell repertoire features associated with broad neutralization, we performed RNA sequencing of the B cell receptors (BCRs) of HCV E2-reactive B cells of HCV-infected individuals with either high or low plasma neutralizing breadth. We then produced a monoclonal antibody (mAb) expressed by pairing the most abundant heavy and light chains from public clonotypes identified among clearance, high neutralization subjects.ResultsWe found distinctive BCR features associated with broad neutralization of HCV, including long heavy chain complementarity determining region 3 (CDRH3) regions, specific VH gene usage, increased frequencies of somatic hypermutation, and particular VH gene mutations. Most intriguing, we identified many E2-reactive public BCR clonotypes (heavy and light chain clones with the same V and J-genes and identical CDR3 sequences) present only in subjects who produced highly neutralizing plasma. The majority of these public clonotypes were shared by two subjects who cleared infection. A mAb expressing the most abundant public heavy and light chains from these clearance, high neutralization subjects had features enriched in high neutralization clonotypes, such as increased somatic hypermutation frequency and usage of IGHV1-69, and was cross-neutralizing.DiscussionTogether, these results demonstrate distinct BCR repertoires associated with high plasma neutralizing capacity. Further characterization of the molecular features and function of these antibodies can inform HCV vaccine development.

【 授权许可】

Unknown   
Copyright © 2023 Skinner, Ogega, Frumento, Clark, Paul, Yegnasubramanian, Schuebel, Meyers, Gupta, Wheelan, Cox, Crowe, Ray and Bailey