Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization.
B-Lymphocytes
/ immunology
Broadly Neutralizing Antibodies
/ chemistry
Complementarity Determining Regions
/ chemistry
Epitopes
Female
Genotype
Hepacivirus
/ genetics
Hepatitis C
/ immunology
Hepatitis C Antibodies
/ chemistry
Humans
Immunoglobulin Heavy Chains
/ chemistry
Male
Middle Aged
Mutation
Viral Envelope Proteins
/ chemistry
HCV
V(H)1-69
elite neutralizer
hepatitis C virus
machine learning
monoclonal antibody
neutralizing antibody
single B cell analysis
somatic mutation
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
08 02 2022
08 02 2022
Historique:
received:
16
07
2021
revised:
21
10
2021
accepted:
06
12
2021
pubmed:
7
1
2022
medline:
15
3
2022
entrez:
6
1
2022
Statut:
ppublish
Résumé
The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%-5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.
Identifiants
pubmed: 34990590
pii: S1074-7613(21)00536-7
doi: 10.1016/j.immuni.2021.12.003
pmc: PMC10089621
mid: NIHMS1883540
pii:
doi:
Substances chimiques
Broadly Neutralizing Antibodies
0
Complementarity Determining Regions
0
Epitopes
0
Hepatitis C Antibodies
0
Immunoglobulin Heavy Chains
0
Viral Envelope Proteins
0
glycoprotein E2, Hepatitis C virus
157184-61-7
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
341-354.e7Subventions
Organisme : NIAID NIH HHS
ID : K99 AI153465
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI127469
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Reported antibodies are in the process of being patented.
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