Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors

Fernando Aleman, Netanel Tzarum, Leopold Kong, Kenna Nagy, Jiang Zhu, Ian A. Wilson*, Mansun Law

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Elicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. Six of the mAbs recognize the conserved E2 antigenic site 412–423 (AS412) and cross-neutralize diverse HCV genotypes. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Intriguingly, the anti-HCV activity of one antibody lineage is associated with maturation of the light chain (LC), whereas the other lineage is dependent on heavy-chain (HC) maturation. Crystal structures of GL precursors of the LC-dependent lineage in complex with AS412 offer critical insights into the maturation process of bnAbs to HCV, providing a scientific foundation for utilizing the mouse model to study AS412-targeting vaccine candidates.

Original languageAmerican English
Pages (from-to)7569-7574
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number29
DOIs
StatePublished - 17 Jul 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.

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