The University of Southampton
University of Southampton Institutional Repository

Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers

Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers
Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers

The HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies.

Journal Article
2211-1247
3324-3338.e5
Aldon, Yoann
be3f0565-c213-44af-973d-3f53b871add4
McKay, Paul F.
563bfbd2-7285-4ad4-a500-a163f9101c36
Allen, Joel
c873d886-2a66-475b-ae04-57a10b37e716
Ozorowski, Gabriel
9d448a80-7310-4b30-ba44-ee8b18222a02
Felfödiné Lévai, Réka
512c8eaa-7327-4bf2-a57f-21851d3c847b
Tolazzi, Monica
fc80a6b8-b884-4639-9403-05f9af68c681
Rogers, Paul
45953a28-19db-4e57-89ca-77af82bd8165
He, Linling
c873e7ef-37de-4629-b646-19e06d13e38f
de Val, Natalia
17ca4fc8-dfab-41dc-aa68-26de0e9a265c
Fábián, Katalin
a94e709d-d690-4f5b-96fe-32a8f1499e05
Scarlatti, Gabriella
3a2ba4c6-4d7e-4e0d-8018-5dfc3e6bb0cd
Zhu, Jiang
65e84bc5-4a0e-4318-b7ce-86b9332a8a85
Ward, Andrew B.
7b743524-72d4-448d-b645-11c55782b656
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Shattock, Robin J.
e102792f-de49-4b2c-bf53-ada9f5521603
Aldon, Yoann
be3f0565-c213-44af-973d-3f53b871add4
McKay, Paul F.
563bfbd2-7285-4ad4-a500-a163f9101c36
Allen, Joel
c873d886-2a66-475b-ae04-57a10b37e716
Ozorowski, Gabriel
9d448a80-7310-4b30-ba44-ee8b18222a02
Felfödiné Lévai, Réka
512c8eaa-7327-4bf2-a57f-21851d3c847b
Tolazzi, Monica
fc80a6b8-b884-4639-9403-05f9af68c681
Rogers, Paul
45953a28-19db-4e57-89ca-77af82bd8165
He, Linling
c873e7ef-37de-4629-b646-19e06d13e38f
de Val, Natalia
17ca4fc8-dfab-41dc-aa68-26de0e9a265c
Fábián, Katalin
a94e709d-d690-4f5b-96fe-32a8f1499e05
Scarlatti, Gabriella
3a2ba4c6-4d7e-4e0d-8018-5dfc3e6bb0cd
Zhu, Jiang
65e84bc5-4a0e-4318-b7ce-86b9332a8a85
Ward, Andrew B.
7b743524-72d4-448d-b645-11c55782b656
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Shattock, Robin J.
e102792f-de49-4b2c-bf53-ada9f5521603

Aldon, Yoann, McKay, Paul F., Allen, Joel, Ozorowski, Gabriel, Felfödiné Lévai, Réka, Tolazzi, Monica, Rogers, Paul, He, Linling, de Val, Natalia, Fábián, Katalin, Scarlatti, Gabriella, Zhu, Jiang, Ward, Andrew B., Crispin, Max and Shattock, Robin J. (2018) Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers. Cell Reports, 24 (12), 3324-3338.e5. (doi:10.1016/j.celrep.2018.08.051).

Record type: Article

Abstract

The HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies.

Text
1-s2.0-S2211124718313378-main - Version of Record
Available under License Creative Commons Attribution.
Download (5MB)

More information

Accepted/In Press date: 17 August 2018
Published date: 18 September 2018
Additional Information: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Keywords: Journal Article

Identifiers

Local EPrints ID: 429211
URI: https://eprints.soton.ac.uk/id/eprint/429211
ISSN: 2211-1247
PURE UUID: 4584e0a4-70d3-4bea-903f-e903039f6d79
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 22 Mar 2019 17:30
Last modified: 09 Dec 2019 17:43

Export record

Altmetrics

Contributors

Author: Yoann Aldon
Author: Paul F. McKay
Author: Joel Allen
Author: Gabriel Ozorowski
Author: Réka Felfödiné Lévai
Author: Monica Tolazzi
Author: Paul Rogers
Author: Linling He
Author: Natalia de Val
Author: Katalin Fábián
Author: Gabriella Scarlatti
Author: Jiang Zhu
Author: Andrew B. Ward
Author: Max Crispin ORCID iD
Author: Robin J. Shattock

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×