Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.
AIDS Vaccines
/ immunology
Animals
Antibodies, Neutralizing
/ immunology
B-Lymphocytes
/ immunology
CD4 Antigens
/ chemistry
Complement C3
/ immunology
Cross-Priming
/ immunology
Epitopes
/ immunology
Glycosylation
HIV Antibodies
/ immunology
HIV Infections
/ immunology
HIV-1
/ immunology
Humans
Immunoglobulin G
/ immunology
Liposomes
Models, Molecular
Neutralization Tests
Polysaccharides
/ immunology
Protein Binding
Protein Conformation
Rabbits
env Gene Products, Human Immunodeficiency Virus
/ administration & dosage
1C2
E70
Env
HIV-1
NFL
bNAbs
glycan deletion
liposomes
trimer
vaccine
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
19 11 2019
19 11 2019
Historique:
received:
15
07
2019
revised:
04
10
2019
accepted:
22
10
2019
pubmed:
17
11
2019
medline:
23
1
2020
entrez:
17
11
2019
Statut:
ppublish
Résumé
The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.
Identifiants
pubmed: 31732167
pii: S1074-7613(19)30452-2
doi: 10.1016/j.immuni.2019.10.008
pmc: PMC6891888
pii:
doi:
Substances chimiques
AIDS Vaccines
0
Antibodies, Neutralizing
0
CD4 Antigens
0
Complement C3
0
Epitopes
0
HIV Antibodies
0
Immunoglobulin G
0
Liposomes
0
Polysaccharides
0
env Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
915-929.e7Subventions
Organisme : NIAID NIH HHS
ID : F31 AI131873
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI104722
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136621
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI100663
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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