A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
11
08
2022
accepted:
09
01
2023
revised:
01
02
2023
pubmed:
21
1
2023
medline:
4
2
2023
entrez:
20
1
2023
Statut:
epublish
Résumé
Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines.
Identifiants
pubmed: 36662906
doi: 10.1371/journal.ppat.1011107
pii: PPATHOGENS-D-22-01400
pmc: PMC9891502
doi:
Substances chimiques
Antibodies, Neutralizing
0
Antibodies, Viral
0
Cytomegalovirus Vaccines
0
Receptors, Antigen, B-Cell
0
Viral Envelope Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011107Subventions
Organisme : NIAID NIH HHS
ID : T32 AI007392
Pays : United States
Organisme : NICHD NIH HHS
ID : F30 HD100170
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI147992
Pays : United States
Informations de copyright
Copyright: © 2023 Jenks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.A.J. has been a paid invited speaker by Moderna x Popsugar. S.R.P. serves as a consultant for Moderna, Merck, Dynavax, Pfizer, and Hookipa CMV vaccine programs and has a sponsored research program on CMV vaccine immunogenicity with Moderna and Merck. J.A.J., K.W., and S.R.P. submitted a provisional patent (#9878-01-US) for antibodies described in this manuscript.
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