Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins.

Abstract

Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.

• Authors: Fang Chen, Netanel Tzarum, Xiaohe Lin, Erick Giang, Rodrigo Velázquez-Moctezuma, Elias H Augestad, Kenna Nagy, Linling He, Mayda Hernandez, Mallorie E Fouch, Ariadna Grinyó, Deborah Chavez, Benjamin J Doranz, Jannick Prentoe, Robyn L Stanfield, Robert Lanford, Jens Bukh, Ian A Wilson, Jiang Zhu, Mansun Law
• Journal: Immunity (Immunity) Vol. 54 Issue 4 Pg. 781-796.e4 (04 13 2021) ISSN: 1097-4180 [Electronic] United States
• PMID: 33675683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Neutralizing
• Epitopes
• Glycoproteins
• IGHV1-69 protein, human
• Receptors, Antigen, B-Cell
• Viral Envelope Proteins

Topics

• Animals
• Antibodies, Neutralizing (immunology)
• B-Lymphocytes (immunology)
• CHO Cells
• Cell Line
• Cricetulus
• Epitopes (immunology)
• Germ Cells (immunology)
• Glycoproteins (immunology)
• HEK293 Cells
• Hepacivirus (immunology)
• Hepatitis C (immunology, virology)
• Humans
• Longitudinal Studies
• Macaca mulatta (immunology, virology)
• Receptors, Antigen, B-Cell (immunology)
• Vaccination (methods)
• Viral Envelope Proteins (immunology)