Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

Timothy M. Reichart; Michael M. Baksh; Jin Kyu Rhee; Jason D. Fiedler; Stephen G. Sligar; M. G. Finn; Michael B. Zwick; Philip E. Dawson

doi:10.1002/anie.201508421

Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

Timothy M. Reichart, Michael M. Baksh, Jin Kyu Rhee, Jason D. Fiedler, Stephen G. Sligar, M. G. Finn, Michael B. Zwick, Philip E. Dawson

Food Science and Biotechnology

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

The membrane-proximal external region (MPER) of HIV gp41 is an established target of antibodies that neutralize a broad range of HIV isolates. To evaluate the role of the transmembrane (TM) domain, synthetic MPER-derived peptides were incorporated into lipid nanoparticles using natural and designed TM domains, and antibody affinity was measured using immobilized and solution-based techniques. Peptides incorporating the native HIV TM domain exhibit significantly stronger interactions with neutralizing antibodies than peptides with a monomeric TM domain. Furthermore, a peptide with a trimeric, three-helix bundle TM domain recapitulates the binding profile of the native sequence. These studies suggest that neutralizing antibodies can bind the MPER when the TM domain is a three-helix bundle and this presentation could influence the binding of neutralizing antibodies to the virus. Lipid-bilayer presentation of viral antigens in Nanodiscs is a new platform for evaluating neutralizing antibodies.

Original language	English
Pages (from-to)	2688-2692
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	55
Issue number	8
DOIs	https://doi.org/10.1002/anie.201508421
State	Published - 18 Feb 2016

Bibliographical note

Funding Information:
This research was supported by the California HIV/AIDS Research Grants Program, D10-SRI-30 (T.M.R.), International AIDS Vaccine Initiative (P.E.D.), and NIH EB015663 (M.G.F.), GM33775 (S.G.S.), AI114401 (M.B.Z.), and GM098871 (P.E.D.). We thank V. Mitch Luna, C. David Stout, Johannes S. Gach, Arthur S. Kim and Florence Brunel for assistance and advice.

Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

HIV
antibodies
membrane proteins
nanostructures
peptides

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title = "Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding",

abstract = "The membrane-proximal external region (MPER) of HIV gp41 is an established target of antibodies that neutralize a broad range of HIV isolates. To evaluate the role of the transmembrane (TM) domain, synthetic MPER-derived peptides were incorporated into lipid nanoparticles using natural and designed TM domains, and antibody affinity was measured using immobilized and solution-based techniques. Peptides incorporating the native HIV TM domain exhibit significantly stronger interactions with neutralizing antibodies than peptides with a monomeric TM domain. Furthermore, a peptide with a trimeric, three-helix bundle TM domain recapitulates the binding profile of the native sequence. These studies suggest that neutralizing antibodies can bind the MPER when the TM domain is a three-helix bundle and this presentation could influence the binding of neutralizing antibodies to the virus. Lipid-bilayer presentation of viral antigens in Nanodiscs is a new platform for evaluating neutralizing antibodies.",

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author = "Reichart, {Timothy M.} and Baksh, {Michael M.} and Rhee, {Jin Kyu} and Fiedler, {Jason D.} and Sligar, {Stephen G.} and Finn, {M. G.} and Zwick, {Michael B.} and Dawson, {Philip E.}",

note = "Funding Information: This research was supported by the California HIV/AIDS Research Grants Program, D10-SRI-30 (T.M.R.), International AIDS Vaccine Initiative (P.E.D.), and NIH EB015663 (M.G.F.), GM33775 (S.G.S.), AI114401 (M.B.Z.), and GM098871 (P.E.D.). We thank V. Mitch Luna, C. David Stout, Johannes S. Gach, Arthur S. Kim and Florence Brunel for assistance and advice. Publisher Copyright: {\textcopyright} 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

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AB - The membrane-proximal external region (MPER) of HIV gp41 is an established target of antibodies that neutralize a broad range of HIV isolates. To evaluate the role of the transmembrane (TM) domain, synthetic MPER-derived peptides were incorporated into lipid nanoparticles using natural and designed TM domains, and antibody affinity was measured using immobilized and solution-based techniques. Peptides incorporating the native HIV TM domain exhibit significantly stronger interactions with neutralizing antibodies than peptides with a monomeric TM domain. Furthermore, a peptide with a trimeric, three-helix bundle TM domain recapitulates the binding profile of the native sequence. These studies suggest that neutralizing antibodies can bind the MPER when the TM domain is a three-helix bundle and this presentation could influence the binding of neutralizing antibodies to the virus. Lipid-bilayer presentation of viral antigens in Nanodiscs is a new platform for evaluating neutralizing antibodies.

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Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding

Abstract

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Keywords

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