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Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability

Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability
Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination. Eliciting broadly neutralizing HIV antibodies by vaccination remains a challenge. Dubrovskaya et al. use an immunization regimen incorporating targeted N-glycan removal and heterologous prime:boosting with NFL trimer-liposomes in rabbits to elicit broadly neutralizing responses to cross-conserved HIV-1 epitopes, including an antibody with 87% neutralization breadth. Further structural analyses highlight similarities between the vaccine-elicited antibodies and the human broadly neutralizing antibodies.

1C2, bNAbs, E70, Env, glycan deletion, HIV-1, liposomes, NFL, trimer, vaccine
1074-7613
915-929.e7
Dubrovskaya, Viktoriya
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Tran, Karen
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Ozorowski, Gabriel
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Guenaga, Javier
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Wilson, Richard
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Bale, Shridhar
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Cottrell, Christopher A.
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Turner, Hannah L.
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Seabright, Gemma
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O'Dell, Sijy
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Torres, Jonathan L.
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Yang, Lifei
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Feng, Yu
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Leaman, Daniel P.
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Vázquez Bernat, Néstor
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Liban, Tyler
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Louder, Mark
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McKee, Krisha
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Bailer, Robert T.
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Movsesyan, Arlette
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Doria-Rose, Nicole A.
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Pancera, Marie
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Zwick, Michael B.
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Crispin, Max
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Ward, Andrew B.
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Wyatt, Richard T.
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Dubrovskaya, Viktoriya
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Tran, Karen
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Ozorowski, Gabriel
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Guenaga, Javier
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Wilson, Richard
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Bale, Shridhar
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Cottrell, Christopher A.
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Turner, Hannah L.
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Seabright, Gemma
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O'Dell, Sijy
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Torres, Jonathan L.
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Yang, Lifei
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Feng, Yu
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Leaman, Daniel P.
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Vázquez Bernat, Néstor
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Liban, Tyler
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Louder, Mark
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McKee, Krisha
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Bailer, Robert T.
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Movsesyan, Arlette
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Doria-Rose, Nicole A.
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Pancera, Marie
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Karlsson Hedestam, Gunilla B.
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Zwick, Michael B.
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Crispin, Max
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Mascola, John R.
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Ward, Andrew B.
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Wyatt, Richard T.
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Dubrovskaya, Viktoriya, Tran, Karen, Ozorowski, Gabriel, Guenaga, Javier, Wilson, Richard, Bale, Shridhar, Cottrell, Christopher A., Turner, Hannah L., Seabright, Gemma, O'Dell, Sijy, Torres, Jonathan L., Yang, Lifei, Feng, Yu, Leaman, Daniel P., Vázquez Bernat, Néstor, Liban, Tyler, Louder, Mark, McKee, Krisha, Bailer, Robert T., Movsesyan, Arlette, Doria-Rose, Nicole A., Pancera, Marie, Karlsson Hedestam, Gunilla B., Zwick, Michael B., Crispin, Max, Mascola, John R., Ward, Andrew B. and Wyatt, Richard T. (2019) Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability. Immunity, 51 (5), 915-929.e7. (doi:10.1016/j.immuni.2019.10.008).

Record type: Article

Abstract

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination. Eliciting broadly neutralizing HIV antibodies by vaccination remains a challenge. Dubrovskaya et al. use an immunization regimen incorporating targeted N-glycan removal and heterologous prime:boosting with NFL trimer-liposomes in rabbits to elicit broadly neutralizing responses to cross-conserved HIV-1 epitopes, including an antibody with 87% neutralization breadth. Further structural analyses highlight similarities between the vaccine-elicited antibodies and the human broadly neutralizing antibodies.

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Dubrovskaya_Immunity_2019 - Version of Record
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More information

Accepted/In Press date: 22 October 2019
e-pub ahead of print date: 12 November 2019
Published date: 19 November 2019
Keywords: 1C2, bNAbs, E70, Env, glycan deletion, HIV-1, liposomes, NFL, trimer, vaccine

Identifiers

Local EPrints ID: 436383
URI: http://eprints.soton.ac.uk/id/eprint/436383
ISSN: 1074-7613
PURE UUID: d4ff4bb7-e0a5-443e-937f-9ab916eb98b3
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 09 Dec 2019 17:30
Last modified: 26 Nov 2021 03:11

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Contributors

Author: Viktoriya Dubrovskaya
Author: Karen Tran
Author: Gabriel Ozorowski
Author: Javier Guenaga
Author: Richard Wilson
Author: Shridhar Bale
Author: Christopher A. Cottrell
Author: Hannah L. Turner
Author: Gemma Seabright
Author: Sijy O'Dell
Author: Jonathan L. Torres
Author: Lifei Yang
Author: Yu Feng
Author: Daniel P. Leaman
Author: Néstor Vázquez Bernat
Author: Tyler Liban
Author: Mark Louder
Author: Krisha McKee
Author: Robert T. Bailer
Author: Arlette Movsesyan
Author: Nicole A. Doria-Rose
Author: Marie Pancera
Author: Gunilla B. Karlsson Hedestam
Author: Michael B. Zwick
Author: Max Crispin ORCID iD
Author: John R. Mascola
Author: Andrew B. Ward
Author: Richard T. Wyatt

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