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HIV-1 vaccine design through minimizing envelope metastability

HIV-1 vaccine design through minimizing envelope metastability
HIV-1 vaccine design through minimizing envelope metastability

Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTO with BG505 gp41ECTO of the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/ founder viruses and UFO trimers containing a consensus-based ancestral gp41ECTO suggest an evolutionary root of metastability. The gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.

2375-2548
He, Linling
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Kumar, Sonu
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Allen, Joel D.
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Huang, Deli
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Lin, Xiaohe
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Mann, Colin J.
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Saye-Francisco, Karen L.
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Copps, Jeffrey
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Sarkar, Anita
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Blizard, Gabrielle S.
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Ozorowski, Gabriel
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Sok, Devin
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Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Ward, Andrew B.
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Nemazee, David
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Burton, Dennis R.
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Wilson, Ian A.
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Zhu, Jiang
65e84bc5-4a0e-4318-b7ce-86b9332a8a85
He, Linling
c873e7ef-37de-4629-b646-19e06d13e38f
Kumar, Sonu
3ef7ede8-6dcc-4ce3-8ab5-70e67b230ba7
Allen, Joel D.
c873d886-2a66-475b-ae04-57a10b37e716
Huang, Deli
1ff3c1ab-6507-437c-9124-ce46d6abc08d
Lin, Xiaohe
2ef60f28-2161-4cd0-b96a-9dd8eed6a0d2
Mann, Colin J.
b8d0b9f2-f440-4028-b898-24a457a11b05
Saye-Francisco, Karen L.
b5023598-5298-4aef-ae58-887cacd588fb
Copps, Jeffrey
05d24804-b883-4b53-b688-f27f4f55c076
Sarkar, Anita
352d5d52-a80a-4e15-afc1-766dc28e0fb9
Blizard, Gabrielle S.
50e76277-4f32-4013-9bde-f4a21f3b8428
Ozorowski, Gabriel
9d448a80-7310-4b30-ba44-ee8b18222a02
Sok, Devin
036d5259-d0a2-45ea-8436-f4c5a7deafe0
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Ward, Andrew B.
7b743524-72d4-448d-b645-11c55782b656
Nemazee, David
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Burton, Dennis R.
a628ce77-b694-4e3c-86a5-11f4e20e1c7c
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Zhu, Jiang
65e84bc5-4a0e-4318-b7ce-86b9332a8a85

He, Linling, Kumar, Sonu, Allen, Joel D., Huang, Deli, Lin, Xiaohe, Mann, Colin J., Saye-Francisco, Karen L., Copps, Jeffrey, Sarkar, Anita, Blizard, Gabrielle S., Ozorowski, Gabriel, Sok, Devin, Crispin, Max, Ward, Andrew B., Nemazee, David, Burton, Dennis R., Wilson, Ian A. and Zhu, Jiang (2018) HIV-1 vaccine design through minimizing envelope metastability. Science Advances, 4 (11), [eaau6769]. (doi:10.1126/sciadv.aau6769).

Record type: Article

Abstract

Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTO with BG505 gp41ECTO of the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/ founder viruses and UFO trimers containing a consensus-based ancestral gp41ECTO suggest an evolutionary root of metastability. The gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.

Text
eaau6769.full - Version of Record
Available under License Creative Commons Attribution.
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More information

Accepted/In Press date: 19 October 2018
e-pub ahead of print date: 21 November 2018

Identifiers

Local EPrints ID: 426931
URI: http://eprints.soton.ac.uk/id/eprint/426931
ISSN: 2375-2548
PURE UUID: 35c0e60f-612e-4d93-9814-b510fd9f4f42
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 18 Dec 2018 17:30
Last modified: 26 Nov 2021 03:11

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Contributors

Author: Linling He
Author: Sonu Kumar
Author: Joel D. Allen
Author: Deli Huang
Author: Xiaohe Lin
Author: Colin J. Mann
Author: Karen L. Saye-Francisco
Author: Jeffrey Copps
Author: Anita Sarkar
Author: Gabrielle S. Blizard
Author: Gabriel Ozorowski
Author: Devin Sok
Author: Max Crispin ORCID iD
Author: Andrew B. Ward
Author: David Nemazee
Author: Dennis R. Burton
Author: Ian A. Wilson
Author: Jiang Zhu

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