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Closing and opening holes in the glycan shield of HIV-1 envelope glycoprotein SOSIP trimers can redirect the neutralizing antibody response to the newly unmasked epitopes

Closing and opening holes in the glycan shield of HIV-1 envelope glycoprotein SOSIP trimers can redirect the neutralizing antibody response to the newly unmasked epitopes
Closing and opening holes in the glycan shield of HIV-1 envelope glycoprotein SOSIP trimers can redirect the neutralizing antibody response to the newly unmasked epitopes

In HIV-1 vaccine research, native-like, soluble envelope glycoprotein SOSIP trimers are widely used for immunizing animals. The epitopes of autologous neutralizing antibodies (NAbs) induced by the BG505 and B41 SOSIP trimers in rabbits and macaques have been mapped to a few holes in the glycan shields that cover most of the protein surfaces. For BG505 trimers, the dominant autologous NAb epitope in rabbits involves residues that line a cavity caused by the absence of a glycan at residue 241. Here, we blocked this epitope in BG505 SOSIPv4.1 trimer immunogens by knocking in an N-linked glycan at residue 241. We then opened holes elsewhere on the trimer by knocking out single N-linked glycans at residues 197, 234, 276, 332, and 355 and found that NAb responses induced by the 241-glycan-bearing BG505 trimers were frequently redirected to the newly opened sites. The strongest evidence for redirection of the NAb response to neoepitopes, through the opening and closing of glycan holes, was obtained from trimer immunogen groups with the highest occupancy of the N241 site. We also attempted to knock in the N289-glycan to block the sole autologous NAb epitope on the B41 SOSIP.v4.1 trimer. Although a retrospective analysis showed that the new N289-glycan site was substantially underoccupied, we found some evidence for redirection of the NAb response to a neoepitope when this site was knocked in and the N356-glycan site knocked out. In neither study, however, was redirection associated with increased neutralization of heterologous tier 2 viruses.IMPORTANCE Engineered SOSIP trimers mimic envelope-glycoprotein spikes, which stud the surface of HIV-1 particles and mediate viral entry into cells. When used for immunizing test animals, they elicit antibodies that neutralize resistant sequence-matched HIV-1 isolates. These neutralizing antibodies recognize epitopes in holes in the glycan shield that covers the trimer. Here, we added glycans to block the most immunogenic neutralization epitopes on BG505 and B41 SOSIP trimers. In addition, we removed selected other glycans to open new holes that might expose new immunogenic epitopes. We immunized rabbits with the various glycan-modified trimers and then dissected the specificities of the antibody responses. Thus, in principle, the antibody response might be diverted from one site to a more cross-reactive one, which would help in the induction of broadly neutralizing antibodies by HIV-1 vaccines based on envelope glycoproteins.

Journal Article
0022-538X
Ringe, Rajesh P.
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Pugach, Pavel
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Cottrell, Christopher A.
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LaBranche, Celia C.
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Seabright, Gemma E.
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Ketas, Thomas J.
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Ozorowski, Gabriel
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Kumar, Sonu
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Schorcht, Anna
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van Gils, Marit J.
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Crispin, Max
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Montefiori, David C.
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Wilson, Ian A.
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Ward, Andrew B.
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Sanders, Rogier W.
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Klasse, Per J.
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Moore, John P.
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Ringe, Rajesh P.
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Pugach, Pavel
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Cottrell, Christopher A.
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LaBranche, Celia C.
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Seabright, Gemma E.
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Ketas, Thomas J.
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Ozorowski, Gabriel
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Kumar, Sonu
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Schorcht, Anna
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van Gils, Marit J.
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Crispin, Max
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Montefiori, David C.
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Wilson, Ian A.
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Ward, Andrew B.
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Sanders, Rogier W.
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Klasse, Per J.
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Moore, John P.
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Ringe, Rajesh P., Pugach, Pavel, Cottrell, Christopher A., LaBranche, Celia C., Seabright, Gemma E., Ketas, Thomas J., Ozorowski, Gabriel, Kumar, Sonu, Schorcht, Anna, van Gils, Marit J., Crispin, Max, Montefiori, David C., Wilson, Ian A., Ward, Andrew B., Sanders, Rogier W., Klasse, Per J. and Moore, John P. (2019) Closing and opening holes in the glycan shield of HIV-1 envelope glycoprotein SOSIP trimers can redirect the neutralizing antibody response to the newly unmasked epitopes. Journal of Virology, 93 (4). (doi:10.1128/JVI.01656-18).

Record type: Article

Abstract

In HIV-1 vaccine research, native-like, soluble envelope glycoprotein SOSIP trimers are widely used for immunizing animals. The epitopes of autologous neutralizing antibodies (NAbs) induced by the BG505 and B41 SOSIP trimers in rabbits and macaques have been mapped to a few holes in the glycan shields that cover most of the protein surfaces. For BG505 trimers, the dominant autologous NAb epitope in rabbits involves residues that line a cavity caused by the absence of a glycan at residue 241. Here, we blocked this epitope in BG505 SOSIPv4.1 trimer immunogens by knocking in an N-linked glycan at residue 241. We then opened holes elsewhere on the trimer by knocking out single N-linked glycans at residues 197, 234, 276, 332, and 355 and found that NAb responses induced by the 241-glycan-bearing BG505 trimers were frequently redirected to the newly opened sites. The strongest evidence for redirection of the NAb response to neoepitopes, through the opening and closing of glycan holes, was obtained from trimer immunogen groups with the highest occupancy of the N241 site. We also attempted to knock in the N289-glycan to block the sole autologous NAb epitope on the B41 SOSIP.v4.1 trimer. Although a retrospective analysis showed that the new N289-glycan site was substantially underoccupied, we found some evidence for redirection of the NAb response to a neoepitope when this site was knocked in and the N356-glycan site knocked out. In neither study, however, was redirection associated with increased neutralization of heterologous tier 2 viruses.IMPORTANCE Engineered SOSIP trimers mimic envelope-glycoprotein spikes, which stud the surface of HIV-1 particles and mediate viral entry into cells. When used for immunizing test animals, they elicit antibodies that neutralize resistant sequence-matched HIV-1 isolates. These neutralizing antibodies recognize epitopes in holes in the glycan shield that covers the trimer. Here, we added glycans to block the most immunogenic neutralization epitopes on BG505 and B41 SOSIP trimers. In addition, we removed selected other glycans to open new holes that might expose new immunogenic epitopes. We immunized rabbits with the various glycan-modified trimers and then dissected the specificities of the antibody responses. Thus, in principle, the antibody response might be diverted from one site to a more cross-reactive one, which would help in the induction of broadly neutralizing antibodies by HIV-1 vaccines based on envelope glycoproteins.

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Ringe_et_al_Marked_up_Manuscript - Accepted Manuscript
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Accepted/In Press date: 16 November 2018
Published date: 15 February 2019
Keywords: Journal Article

Identifiers

Local EPrints ID: 428934
URI: http://eprints.soton.ac.uk/id/eprint/428934
ISSN: 0022-538X
PURE UUID: b8879a17-8ef7-4d9e-b075-ff8443554fe5
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

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Date deposited: 14 Mar 2019 17:30
Last modified: 26 Nov 2021 05:50

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Contributors

Author: Rajesh P. Ringe
Author: Pavel Pugach
Author: Christopher A. Cottrell
Author: Celia C. LaBranche
Author: Gemma E. Seabright
Author: Thomas J. Ketas
Author: Gabriel Ozorowski
Author: Sonu Kumar
Author: Anna Schorcht
Author: Marit J. van Gils
Author: Max Crispin ORCID iD
Author: David C. Montefiori
Author: Ian A. Wilson
Author: Andrew B. Ward
Author: Rogier W. Sanders
Author: Per J. Klasse
Author: John P. Moore

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