Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions.
HIV-1 Env
NGS
bNAbs
deletions
germline-targeting
insertions
mouse model
neutralizing antibodies
vaccines
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
18 04 2023
18 04 2023
Historique:
received:
15
09
2022
revised:
23
01
2023
accepted:
17
03
2023
medline:
21
4
2023
pubmed:
13
4
2023
entrez:
12
4
2023
Statut:
ppublish
Résumé
Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.
Identifiants
pubmed: 37044090
pii: S2666-3791(23)00113-1
doi: 10.1016/j.xcrm.2023.101003
pmc: PMC10140475
pii:
doi:
Substances chimiques
Broadly Neutralizing Antibodies
0
Antibodies, Neutralizing
0
HIV Antibodies
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
101003Subventions
Organisme : NIAID NIH HHS
ID : HHSN272201800004C
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI087202
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI100645
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI110657
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI036082
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI144371
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM138396
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 Amsterdam UMC has filed a patent application related to germline-targeting HIV-1 Env trimers.
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