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The glycan hole area of HIV-1 envelope trimers contributes prominently to the induction of autologous neutralization

The glycan hole area of HIV-1 envelope trimers contributes prominently to the induction of autologous neutralization
The glycan hole area of HIV-1 envelope trimers contributes prominently to the induction of autologous neutralization

The HIV-1 envelope glycoprotein trimer (Env) is heavily glycosylated, creating a dense glycan shield that protects the underlying peptidic surface from antibody recognition. The absence of conserved glycans, due to missing potential N-linked glycosylation sites (PNGS), can result in strain-specific, autologous neutralizing antibody (NAb) responses. Here we sought to gain a deeper understanding of the autologous neutralization by introducing holes in the otherwise dense glycan shields of the AMC011 and AMC016 SOSIP trimers. Specifically, when we knocked out the N130 and N289 glycans, which are absent from the well-characterized B41 SOSIP trimer, we observed stronger autologous NAb responses. We also analyzed the highly variable NAb responses induced in rabbits by diverse SOSIP trimers from subtypes A, B and C. Statistical analysis, using a linear regression analysis, revealed that the cumulative area exposed on a trimer by glycan holes correlates with the magnitude of the autologous NAb response. Importance 40 years after the first description of HIV-1 the search for a protective vaccine is still ongoing. The sole target for antibodies that can neutralize the virus are the trimeric envelope glycoproteins (Env) located on the viral surface. The glycoprotein surface is covered with glycans that shield off the underlying protein components from recognition by the immune system. However, the Env trimers of some viral strains have holes in the glycan shield. Immunized animals developed antibodies against such glycan holes. These antibodies are generally strain-specific. Here we sought to gain a deeper understanding of what drives these specific immune responses. First, we show that strain-specific neutralizing antibody responses can be increased by creating artificial holes in the glycan shield. Second, when studying a diverse set of Env trimers with different characteristics, we found that the surface area of the glycan holes contributes prominently to the induction of strain-specific neutralizing antibodies.

0022-538X
e0155221
Schorcht, Anna
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Cottrell, Christopher A
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Pugach, Pavel
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Ringe, Rajesh P
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Han, Alvin X
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Allen, Joel D
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van den Kerkhof, Tom L G M
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Seabright, Gemma E
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Schermer, Edith E
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van Schooten, Jelle
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LaBranche, Celia C
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Ozorowski, Gabriel
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de Val, Natalia
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Bader, Daniel L V
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Schuitemaker, Hanneke
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Russell, Colin A
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Montefiori, David C
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van Gils, Marit J
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Crispin, Max
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Moore, John P
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Schorcht, Anna
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Ringe, Rajesh P
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Han, Alvin X
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Allen, Joel D
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van den Kerkhof, Tom L G M
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van Schooten, Jelle
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LaBranche, Celia C
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Ozorowski, Gabriel
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de Val, Natalia
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Bader, Daniel L V
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Schuitemaker, Hanneke
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Russell, Colin A
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van Gils, Marit J
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Crispin, Max
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Klasse, P J
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Ward, Andrew B
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Moore, John P
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Sanders, Rogier W
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Schorcht, Anna, Cottrell, Christopher A, Pugach, Pavel, Ringe, Rajesh P, Han, Alvin X, Allen, Joel D, van den Kerkhof, Tom L G M, Seabright, Gemma E, Schermer, Edith E, Ketas, Thomas J, Burger, Judith A, van Schooten, Jelle, LaBranche, Celia C, Ozorowski, Gabriel, de Val, Natalia, Bader, Daniel L V, Schuitemaker, Hanneke, Russell, Colin A, Montefiori, David C, van Gils, Marit J, Crispin, Max, Klasse, P J, Ward, Andrew B, Moore, John P and Sanders, Rogier W (2022) The glycan hole area of HIV-1 envelope trimers contributes prominently to the induction of autologous neutralization. Journal of Virology, 96 (1), e0155221, [e01552-21]. (doi:10.1128/JVI.01552-21).

Record type: Article

Abstract

The HIV-1 envelope glycoprotein trimer (Env) is heavily glycosylated, creating a dense glycan shield that protects the underlying peptidic surface from antibody recognition. The absence of conserved glycans, due to missing potential N-linked glycosylation sites (PNGS), can result in strain-specific, autologous neutralizing antibody (NAb) responses. Here we sought to gain a deeper understanding of the autologous neutralization by introducing holes in the otherwise dense glycan shields of the AMC011 and AMC016 SOSIP trimers. Specifically, when we knocked out the N130 and N289 glycans, which are absent from the well-characterized B41 SOSIP trimer, we observed stronger autologous NAb responses. We also analyzed the highly variable NAb responses induced in rabbits by diverse SOSIP trimers from subtypes A, B and C. Statistical analysis, using a linear regression analysis, revealed that the cumulative area exposed on a trimer by glycan holes correlates with the magnitude of the autologous NAb response. Importance 40 years after the first description of HIV-1 the search for a protective vaccine is still ongoing. The sole target for antibodies that can neutralize the virus are the trimeric envelope glycoproteins (Env) located on the viral surface. The glycoprotein surface is covered with glycans that shield off the underlying protein components from recognition by the immune system. However, the Env trimers of some viral strains have holes in the glycan shield. Immunized animals developed antibodies against such glycan holes. These antibodies are generally strain-specific. Here we sought to gain a deeper understanding of what drives these specific immune responses. First, we show that strain-specific neutralizing antibody responses can be increased by creating artificial holes in the glycan shield. Second, when studying a diverse set of Env trimers with different characteristics, we found that the surface area of the glycan holes contributes prominently to the induction of strain-specific neutralizing antibodies.

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e-pub ahead of print date: 20 October 2021
Published date: 12 January 2022
Additional Information: Funding Information: The Amsterdam Cohort Studies on HIV Infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, Medical Center Jan van Goyen, and the HIV Focus Center of the DC-Clinics, are part of the Netherlands HIV Monitoring Foundation and financially supported by the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and Environment. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: © 2022 Schorcht et al.

Identifiers

Local EPrints ID: 452230
URI: http://eprints.soton.ac.uk/id/eprint/452230
ISSN: 0022-538X
PURE UUID: f6b879b5-37f2-45cd-8fb3-7e34e972b0e5
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: 30 Nov 2021 17:33
Last modified: 17 Mar 2024 04:09

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Contributors

Author: Anna Schorcht
Author: Christopher A Cottrell
Author: Pavel Pugach
Author: Rajesh P Ringe
Author: Alvin X Han
Author: Joel D Allen ORCID iD
Author: Tom L G M van den Kerkhof
Author: Gemma E Seabright
Author: Edith E Schermer
Author: Thomas J Ketas
Author: Judith A Burger
Author: Jelle van Schooten
Author: Celia C LaBranche
Author: Gabriel Ozorowski
Author: Natalia de Val
Author: Daniel L V Bader
Author: Hanneke Schuitemaker
Author: Colin A Russell
Author: David C Montefiori
Author: Marit J van Gils
Author: Max Crispin ORCID iD
Author: P J Klasse
Author: Andrew B Ward
Author: John P Moore
Author: Rogier W Sanders

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