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.
He, Linling
c873e7ef-37de-4629-b646-19e06d13e38f
Kumar, Sonu
3ef7ede8-6dcc-4ce3-8ab5-70e67b230ba7
Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
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
309d7d83-4b5c-4a55-ac4c-902435d566f4
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
c873e7ef-37de-4629-b646-19e06d13e38f
Kumar, Sonu
3ef7ede8-6dcc-4ce3-8ab5-70e67b230ba7
Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
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
309d7d83-4b5c-4a55-ac4c-902435d566f4
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).
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
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
Catalogue record
Date deposited: 18 Dec 2018 17:30
Last modified: 18 Mar 2024 04:03
Export record
Altmetrics
Contributors
Author:
Linling He
Author:
Sonu Kumar
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:
Andrew B. Ward
Author:
David Nemazee
Author:
Dennis R. Burton
Author:
Ian A. Wilson
Author:
Jiang Zhu
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
