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Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles
Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.

2059-0105
Brouwer, Philip J M
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Antanasijevic, Aleksandar
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de Gast, Marlon
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Allen, Joel D
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Bijl, Tom P L
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Yasmeen, Anila
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Ravichandran, Rashmi
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Burger, Judith A
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Ozorowski, Gabriel
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Torres, Jonathan L
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LaBranche, Celia
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Montefiori, David C
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Ringe, Rajesh P
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van Gils, Marit J
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Moore, John P
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Klasse, Per Johan
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Crispin, Max
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King, Neil P
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Ward, Andrew B
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Sanders, Rogier W
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Brouwer, Philip J M
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Antanasijevic, Aleksandar
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de Gast, Marlon
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Allen, Joel D
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Bijl, Tom P L
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Yasmeen, Anila
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Ravichandran, Rashmi
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Burger, Judith A
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Ozorowski, Gabriel
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Torres, Jonathan L
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LaBranche, Celia
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Montefiori, David C
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Ringe, Rajesh P
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van Gils, Marit J
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Moore, John P
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Klasse, Per Johan
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Crispin, Max
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King, Neil P
19437abf-1af8-4243-975f-0f4cbfeda355
Ward, Andrew B
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Sanders, Rogier W
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Brouwer, Philip J M, Antanasijevic, Aleksandar, de Gast, Marlon, Allen, Joel D, Bijl, Tom P L, Yasmeen, Anila, Ravichandran, Rashmi, Burger, Judith A, Ozorowski, Gabriel, Torres, Jonathan L, LaBranche, Celia, Montefiori, David C, Ringe, Rajesh P, van Gils, Marit J, Moore, John P, Klasse, Per Johan, Crispin, Max, King, Neil P, Ward, Andrew B and Sanders, Rogier W (2021) Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles. NPJ Vaccines, 6 (1), [24]. (doi:10.1038/s41541-021-00285-9).

Record type: Article

Abstract

The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.

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e-pub ahead of print date: 9 February 2021
Published date: 9 February 2021
Additional Information: Funding Information: The authors thank Michel Nussenzweig, James Robinson, Dennis Burton, Peter Kwong, Mark Connors, John Mascola, and William Olson for donating antibodies and reagents directly or through the NIH AIDS Research and Reference Reagent Program. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Ramos B cells from Drs. Li Wu and Vineet N. KewalRaman. We thank Andrew McGuire for kindly sharing the pRRL.EuB29 lentiviral vector that was used to transduce Ramos B cells. This work was supported by the U. S. National Institutes of Health Grant P01 AI110657 (to J.P.M., A.B.W., P.J.K., and R.W. S.) and NIAID Contract #HHSN27201100016C (to D.C.M.); by the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD), grants OPP1111923 and OPP1132237 (to N.K., J.P.M., and R.W.S.), INV-008352/ OPP1153692 (to M.C.), and OPP1115782 (to A.B.W.); by the National Institute for Allergy and Infectious Diseases through the Scripps Consortium for HIV Vaccine Development (CHAVD) grant AI144462 (to M.C.); by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 681137 (to R.W. S. and M.C.); and by the Fondation Dormeur, Vaduz (to R.W.S.). R.W.S. is a recipient of a Vici grant from the Netherlands Organization for Scientific Research (NWO). M.J.G. is a recipient of an AMC Fellowship and a Mathilde Krim Fellowship from the American Foundation for AIDS Research (amfAR) (109514-61-RKVA). The electron microscopy data were collected at Electron Microscopy Facility of the Scripps Research Institute. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 447559
URI: http://eprints.soton.ac.uk/id/eprint/447559
ISSN: 2059-0105
PURE UUID: aeb00058-0683-4408-82be-1f53b47e0706
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: 16 Mar 2021 17:31
Last modified: 17 Mar 2024 04:09

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Contributors

Author: Philip J M Brouwer
Author: Aleksandar Antanasijevic
Author: Marlon de Gast
Author: Joel D Allen ORCID iD
Author: Tom P L Bijl
Author: Anila Yasmeen
Author: Rashmi Ravichandran
Author: Judith A Burger
Author: Gabriel Ozorowski
Author: Jonathan L Torres
Author: Celia LaBranche
Author: David C Montefiori
Author: Rajesh P Ringe
Author: Marit J van Gils
Author: John P Moore
Author: Per Johan Klasse
Author: Max Crispin ORCID iD
Author: Neil P King
Author: Andrew B Ward
Author: Rogier W Sanders

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