A combination of two resistance mechanisms is critical for tick-borne encephalitis virus escape from a broadly neutralizing human antibody.
CP: Immunology
CP: Microbiology
escape mutant
monoclonal antibody
neutralization
tick-borne encephalitis
tick-borne encephalitis virus
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 09 2023
26 09 2023
Historique:
received:
23
05
2023
revised:
26
07
2023
accepted:
31
08
2023
medline:
5
10
2023
pubmed:
16
9
2023
entrez:
16
9
2023
Statut:
ppublish
Résumé
Tick-borne encephalitis virus (TBEV) is a flavivirus that causes human neuroinfections and represents a growing health problem. The human monoclonal antibody T025 targets envelope protein domain III (EDIII) of TBEV and related tick-borne flaviviruses, potently neutralizing TBEV in vitro and in preclinical models, representing a promising candidate for clinical development. We demonstrate that TBEV escape in the presence of T025 or T028 (another EDIII-targeting human monoclonal antibody) results in virus variants of reduced pathogenicity, characterized by distinct sets of amino acid changes in EDII and EDIII that are jointly needed to confer resistance. EDIII substitution K311N impairs formation of a salt bridge critical for T025-epitope interaction. EDII substitution E230K is not on the T025 epitope but likely induces quaternary rearrangements of the virus surface because of repulsion of positively charged residues on the adjacent EDI. A combination of T025 and T028 prevents virus escape and improves neutralization.
Identifiants
pubmed: 37715951
pii: S2211-1247(23)01161-0
doi: 10.1016/j.celrep.2023.113149
pmc: PMC10591882
mid: NIHMS1933926
pii:
doi:
Substances chimiques
Antibodies, Viral
0
Epitopes
0
Antibodies, Monoclonal
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
113149Subventions
Organisme : NIAID NIH HHS
ID : P01 AI138938
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI151698
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI111825
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The Rockefeller University filed a patent application in connection with antibodies T025 and T028, on which M.A., D.F.R., and M.C.N. are inventors.
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