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Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike

Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike
Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike

Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.

cryo-EM, glycan occupancy, HIV-1 vaccine research, mass spectrometry
2211-1247
Derking, Ronald
66536ca3-069b-448e-9703-42202044a04b
Allen, Joel D.
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Cottrell, Christopher A.
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Sliepen, Kwinten
d2551fe9-7d04-459e-85b5-29fc4b35317a
Seabright, Gemma E.
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Lee, Wen Hsin
a30e425f-7907-4f8c-b1e0-682dec238fae
Aldon, Yoann
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Rantalainen, Kimmo
d86844e5-562c-482f-b872-d03eb1631da0
Antanasijevic, Aleksandar
f87b3a62-684c-41e3-8898-5ec80d6d50c3
Copps, Jeffrey
05d24804-b883-4b53-b688-f27f4f55c076
Yasmeen, Anila
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Cupo, Albert
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Cruz Portillo, Victor M.
9e75922a-3b79-4f9a-8711-a49bcc051ec8
Poniman, Meliawati
b4edda07-2297-41c3-813e-4a6dcc97efe1
Bol, Niki
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van der Woude, Patricia
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de Taeye, Steven W.
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van den Kerkhof, Tom L.G.M.
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Klasse, P. J.
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Ozorowski, Gabriel
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van Gils, Marit J.
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Moore, John P.
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Ward, Andrew B.
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Crispin, Max
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Sanders, Rogier W.
d3b67c2c-c725-42e7-b972-50b30be67c74
Derking, Ronald
66536ca3-069b-448e-9703-42202044a04b
Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
Cottrell, Christopher A.
942bfa7b-c09e-459d-a6c2-0d64d55fa230
Sliepen, Kwinten
d2551fe9-7d04-459e-85b5-29fc4b35317a
Seabright, Gemma E.
09e75998-09b0-465f-a059-c89b07f3b2c3
Lee, Wen Hsin
a30e425f-7907-4f8c-b1e0-682dec238fae
Aldon, Yoann
be3f0565-c213-44af-973d-3f53b871add4
Rantalainen, Kimmo
d86844e5-562c-482f-b872-d03eb1631da0
Antanasijevic, Aleksandar
f87b3a62-684c-41e3-8898-5ec80d6d50c3
Copps, Jeffrey
05d24804-b883-4b53-b688-f27f4f55c076
Yasmeen, Anila
2c47f610-f8ab-4b85-b33e-64837c8345cc
Cupo, Albert
aa9f476e-3296-4118-9231-0edc774b8335
Cruz Portillo, Victor M.
9e75922a-3b79-4f9a-8711-a49bcc051ec8
Poniman, Meliawati
b4edda07-2297-41c3-813e-4a6dcc97efe1
Bol, Niki
49aafcf2-62eb-40af-a02d-54d7d0e32239
van der Woude, Patricia
13b39e34-ecb1-459f-af37-3da520bc557a
de Taeye, Steven W.
3ee19998-9ef7-4630-8a9b-da852b834225
van den Kerkhof, Tom L.G.M.
1241dc0d-81ff-441f-adc6-43433e1c402e
Klasse, P. J.
23277bb2-de88-4e9c-9b54-3fb1193e9d9e
Ozorowski, Gabriel
9d448a80-7310-4b30-ba44-ee8b18222a02
van Gils, Marit J.
f2e1e7f1-36a1-4270-8509-d17a10ddb9a6
Moore, John P.
3c26226c-c036-48db-bbd1-828a86b29697
Ward, Andrew B.
78ce5b6a-b852-4ee4-a950-f7ff7b183d83
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Sanders, Rogier W.
d3b67c2c-c725-42e7-b972-50b30be67c74

Derking, Ronald, Allen, Joel D., Cottrell, Christopher A., Sliepen, Kwinten, Seabright, Gemma E., Lee, Wen Hsin, Aldon, Yoann, Rantalainen, Kimmo, Antanasijevic, Aleksandar, Copps, Jeffrey, Yasmeen, Anila, Cupo, Albert, Cruz Portillo, Victor M., Poniman, Meliawati, Bol, Niki, van der Woude, Patricia, de Taeye, Steven W., van den Kerkhof, Tom L.G.M., Klasse, P. J., Ozorowski, Gabriel, van Gils, Marit J., Moore, John P., Ward, Andrew B., Crispin, Max and Sanders, Rogier W. (2021) Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike. Cell Reports, 35 (1), [108933]. (doi:10.1016/j.celrep.2021.108933).

Record type: Article

Abstract

Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.

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Accepted/In Press date: 11 March 2021
e-pub ahead of print date: 6 April 2021
Published date: 6 April 2021
Keywords: cryo-EM, glycan occupancy, HIV-1 vaccine research, mass spectrometry
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Identifiers

Local EPrints ID: 448905
URI: http://eprints.soton.ac.uk/id/eprint/448905
DOI: doi:10.1016/j.celrep.2021.108933
ISSN: 2211-1247
PURE UUID: 5fe08e9a-6676-4887-acd7-03faeeeb499e
ORCID for Joel D. Allen: ORCID iD orcid.org/0000-0003-2547-968X
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

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Date deposited: 10 May 2021 16:32
Last modified: 12 Jul 2024 02:09

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Contributors

Author: Ronald Derking
Author: Joel D. Allen ORCID iD
Author: Christopher A. Cottrell
Author: Kwinten Sliepen
Author: Gemma E. Seabright
Author: Wen Hsin Lee
Author: Yoann Aldon
Author: Kimmo Rantalainen
Author: Aleksandar Antanasijevic
Author: Jeffrey Copps
Author: Anila Yasmeen
Author: Albert Cupo
Author: Victor M. Cruz Portillo
Author: Meliawati Poniman
Author: Niki Bol
Author: Patricia van der Woude
Author: Steven W. de Taeye
Author: Tom L.G.M. van den Kerkhof
Author: P. J. Klasse
Author: Gabriel Ozorowski
Author: Marit J. van Gils
Author: John P. Moore
Author: Andrew B. Ward
Author: Max Crispin ORCID iD
Author: Rogier W. Sanders

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