Design and characterization of a germ-line targeting soluble, native-like, trimeric HIV-1 Env lacking key glycans from the V1V2-loop.
Clade C
Deglycosylation
Envelope glycoprotein
HIV-1
Immunogen design
Trimer
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
05
06
2020
revised:
10
09
2020
accepted:
11
09
2020
pubmed:
20
9
2020
medline:
12
1
2021
entrez:
19
9
2020
Statut:
ppublish
Résumé
The HIV-1 envelope glycoprotein (Env) is the primary target for broadly neutralizing antibodies (bNAbs) which can block infection. The current design strategy of soluble forms of Env in native-like trimeric conformation induces neutralizing antibodies with minimal breadth and potency. Extensive shielding by N-glycans on the surface of the HIV-1 Env acts as an immune evasion mechanism by restricting B cell recognition of conserved neutralizing determinants. An alternate approach is to design Env protein with glycan deletion to expose the protein surface. A stable native-like trimeric Env with glycan holes at potentially immunogenic locations is expected to elicit better induction of germ-line B-cells due to exposure of the immunogenic regions. However, the extent and consequences of glycan removal from the trimer apex that form an important epitope is not explored. In this work, we have designed a construct with glycans deleted from the trimer apex of an Indian clade C origin Env that has previously been characterized for immunogenicity, to understand the impact of deglycosylation on the structural and functional integrity as well as on the antibody binding properties. The V1V2 glycan-deleted protein maintains native-like trimeric conformation with improved accessibility of the V1V2-directed germ-line antibodies. Furthermore, we showed that the protein binds specifically to quaternary conformation-dependent bnAbs but minimally to non-neutralizing antibodies. This study provide an important design aspect of HIV-1 Env-based immunogens with glycan holes in the apex region that could be useful in eliciting apex directed antibodies in immunization studies.
Sections du résumé
BACKGROUND
The HIV-1 envelope glycoprotein (Env) is the primary target for broadly neutralizing antibodies (bNAbs) which can block infection. The current design strategy of soluble forms of Env in native-like trimeric conformation induces neutralizing antibodies with minimal breadth and potency. Extensive shielding by N-glycans on the surface of the HIV-1 Env acts as an immune evasion mechanism by restricting B cell recognition of conserved neutralizing determinants. An alternate approach is to design Env protein with glycan deletion to expose the protein surface.
METHODS
A stable native-like trimeric Env with glycan holes at potentially immunogenic locations is expected to elicit better induction of germ-line B-cells due to exposure of the immunogenic regions. However, the extent and consequences of glycan removal from the trimer apex that form an important epitope is not explored. In this work, we have designed a construct with glycans deleted from the trimer apex of an Indian clade C origin Env that has previously been characterized for immunogenicity, to understand the impact of deglycosylation on the structural and functional integrity as well as on the antibody binding properties.
RESULTS
The V1V2 glycan-deleted protein maintains native-like trimeric conformation with improved accessibility of the V1V2-directed germ-line antibodies. Furthermore, we showed that the protein binds specifically to quaternary conformation-dependent bnAbs but minimally to non-neutralizing antibodies.
CONCLUSIONS
This study provide an important design aspect of HIV-1 Env-based immunogens with glycan holes in the apex region that could be useful in eliciting apex directed antibodies in immunization studies.
Identifiants
pubmed: 32949621
pii: S0304-4165(20)30245-2
doi: 10.1016/j.bbagen.2020.129733
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Epitopes
0
Polysaccharides
0
env Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129733Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.