Automated Design by Structure-Based Stabilization and Consensus Repair to Achieve Prefusion-Closed Envelope Trimers in a Wide Variety of HIV Strains.
ADROITrimer
HIV-1 vaccine
RnS
RnS-DS-SOSIP
conformational stabilization
protein design
repair and stabilize
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
24 11 2020
24 11 2020
Historique:
received:
07
05
2020
revised:
21
09
2020
accepted:
04
11
2020
entrez:
25
11
2020
pubmed:
26
11
2020
medline:
17
12
2021
Statut:
ppublish
Résumé
Soluble envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit neutralizing responses against HIV-1 strains closely related to the immunizing trimer. However, to date such stabilization has succeeded with only a limited number of HIV-1 strains. To address this issue, here we develop ADROITrimer, an automated procedure involving structure-based stabilization and consensus repair, and generate "RnS-DS-SOSIP"-stabilized Envs from 180 diverse Env sequences. The vast majority of these RnS-DS-SOSIP Envs fold into prefusion-closed conformations as judged by antigenic analysis and size exclusion chromatography. Additionally, representative strains from clades AE, B, and C are stabilized in prefusion-closed conformations as shown by negative-stain electron microscopy, and the crystal structure of a clade A strain MI369.A5 Env trimer provides 3.5 Å resolution detail into stabilization and repair mutations. The automated procedure reported herein that yields well-behaved, soluble, prefusion-closed Env trimers from a majority of HIV-1 strains could have substantial impact on the development of an HIV-1 vaccine.
Identifiants
pubmed: 33238130
pii: S2211-1247(20)31421-2
doi: 10.1016/j.celrep.2020.108432
pmc: PMC7714614
mid: NIHMS1649698
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
HIV Antibodies
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, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
108432Subventions
Organisme : Intramural NIH HHS
ID : ZIA AI005024
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC AI005113
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC AI005114
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of Interests These studies were funded in part by Janssen Vaccines and Prevention. L.R., S.B., J.J., and J.P.M.L. are employees of Janssen. L.R. and J.P.M.L. are inventors on an international patent application describing trimer stabilizing HIV envelope protein mutations.
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