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Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens

Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens
Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens

Two-component, self-assembling nanoparticles represent a versatile platform for multivalent presentation of viral antigens. Computational design of protein nanoparticles with differing sizes and geometries enables combination with antigens of choice to test novel multimerization concepts in immunization strategies where the goal is to improve the induction and maturation of neutralizing antibody lineages. Here, we describe detailed antigenic, structural, and functional characterization of computationally designed tetrahedral, octahedral, and icosahedral nanoparticle immunogens displaying trimeric HIV envelope glycoprotein (Env) ectodomains. Env trimers, based on subtype A (BG505) or consensus group M (ConM) sequences and engineered with SOSIP stabilizing mutations, were fused to an underlying trimeric building block of each nanoparticle. Initial screening yielded one icosahedral and two tetrahedral nanoparticle candidates, capable of presenting twenty or four copies of the Env trimer. A number of analyses, including detailed structural characterization by cryo-EM, demonstrated that the nanoparticle immunogens possessed the intended structural and antigenic properties. When the immunogenicity of ConM-SOSIP trimers presented on a two-component tetrahedral nanoparticle or as soluble proteins were compared in rabbits, the two immunogens elicited similar serum antibody binding titers against the trimer component. Neutralizing antibody titers were slightly elevated in the animals given the nanoparticle immunogen and were initially more focused to the trimer apex. Altogether, our findings indicate that tetrahedral nanoparticles can be successfully applied for presentation of HIV Env trimer immunogens; however, the optimal implementation to different immunization strategies remains to be determined..

1553-7366
Antanasijevic, Aleksandar
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Ueda, George
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Brouwer, Philip J.M.
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Copps, Jeffrey
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Huang, Deli
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Allen, Joel D.
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Cottrell, Christopher A.
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Yasmeen, Anila
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Sewall, Leigh M.
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Bontjer, Ilja
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Ketas, Thomas J.
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Turner, Hannah L.
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Berndsen, Zachary T.
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Montefiori, David C.
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Klasse, Per Johan
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Crispin, Max
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Nemazee, David
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Moore, John P.
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Sanders, Rogier W.
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King, Neil P.
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Baker, David
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Ward, Andrew B.
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Antanasijevic, Aleksandar
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Ueda, George
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Brouwer, Philip J.M.
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Copps, Jeffrey
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Huang, Deli
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Allen, Joel D.
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Cottrell, Christopher A.
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Yasmeen, Anila
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Sewall, Leigh M.
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Bontjer, Ilja
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Ketas, Thomas J.
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Turner, Hannah L.
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Berndsen, Zachary T.
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Montefiori, David C.
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Klasse, Per Johan
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Crispin, Max
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Nemazee, David
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Moore, John P.
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Sanders, Rogier W.
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King, Neil P.
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Baker, David
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Ward, Andrew B.
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Antanasijevic, Aleksandar, Ueda, George, Brouwer, Philip J.M., Copps, Jeffrey, Huang, Deli, Allen, Joel D., Cottrell, Christopher A., Yasmeen, Anila, Sewall, Leigh M., Bontjer, Ilja, Ketas, Thomas J., Turner, Hannah L., Berndsen, Zachary T., Montefiori, David C., Klasse, Per Johan, Crispin, Max, Nemazee, David, Moore, John P., Sanders, Rogier W., King, Neil P., Baker, David and Ward, Andrew B. (2020) Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens. PLoS Pathogens, 16 (8), [e1008665]. (doi:10.1371/JOURNAL.PPAT.1008665).

Record type: Article

Abstract

Two-component, self-assembling nanoparticles represent a versatile platform for multivalent presentation of viral antigens. Computational design of protein nanoparticles with differing sizes and geometries enables combination with antigens of choice to test novel multimerization concepts in immunization strategies where the goal is to improve the induction and maturation of neutralizing antibody lineages. Here, we describe detailed antigenic, structural, and functional characterization of computationally designed tetrahedral, octahedral, and icosahedral nanoparticle immunogens displaying trimeric HIV envelope glycoprotein (Env) ectodomains. Env trimers, based on subtype A (BG505) or consensus group M (ConM) sequences and engineered with SOSIP stabilizing mutations, were fused to an underlying trimeric building block of each nanoparticle. Initial screening yielded one icosahedral and two tetrahedral nanoparticle candidates, capable of presenting twenty or four copies of the Env trimer. A number of analyses, including detailed structural characterization by cryo-EM, demonstrated that the nanoparticle immunogens possessed the intended structural and antigenic properties. When the immunogenicity of ConM-SOSIP trimers presented on a two-component tetrahedral nanoparticle or as soluble proteins were compared in rabbits, the two immunogens elicited similar serum antibody binding titers against the trimer component. Neutralizing antibody titers were slightly elevated in the animals given the nanoparticle immunogen and were initially more focused to the trimer apex. Altogether, our findings indicate that tetrahedral nanoparticles can be successfully applied for presentation of HIV Env trimer immunogens; however, the optimal implementation to different immunization strategies remains to be determined..

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Accepted/In Press date: 28 May 2020
Published date: 11 August 2020

Identifiers

Local EPrints ID: 444033
URI: http://eprints.soton.ac.uk/id/eprint/444033
ISSN: 1553-7366
PURE UUID: 8a510854-9072-4b98-aa01-3c08a07f391d
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

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Date deposited: 23 Sep 2020 16:30
Last modified: 27 Apr 2021 01:54

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Contributors

Author: Aleksandar Antanasijevic
Author: George Ueda
Author: Philip J.M. Brouwer
Author: Jeffrey Copps
Author: Deli Huang
Author: Joel D. Allen
Author: Christopher A. Cottrell
Author: Anila Yasmeen
Author: Leigh M. Sewall
Author: Ilja Bontjer
Author: Thomas J. Ketas
Author: Hannah L. Turner
Author: Zachary T. Berndsen
Author: David C. Montefiori
Author: Per Johan Klasse
Author: Max Crispin ORCID iD
Author: David Nemazee
Author: John P. Moore
Author: Rogier W. Sanders
Author: Neil P. King
Author: David Baker
Author: Andrew B. Ward

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