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Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design

Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the...

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Autores principales: Irimia, Adriana, Serra, Andreia M., Sarkar, Anita, Jacak, Ronald, Kalyuzhniy, Oleksandr, Sok, Devin, Saye-Francisco, Karen L., Schiffner, Torben, Tingle, Ryan, Kubitz, Michael, Adachi, Yumiko, Stanfield, Robyn L., Deller, Marc C., Burton, Dennis R., Schief, William R., Wilson, Ian A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338832/
https://www.ncbi.nlm.nih.gov/pubmed/28225819
http://dx.doi.org/10.1371/journal.ppat.1006212
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author Irimia, Adriana
Serra, Andreia M.
Sarkar, Anita
Jacak, Ronald
Kalyuzhniy, Oleksandr
Sok, Devin
Saye-Francisco, Karen L.
Schiffner, Torben
Tingle, Ryan
Kubitz, Michael
Adachi, Yumiko
Stanfield, Robyn L.
Deller, Marc C.
Burton, Dennis R.
Schief, William R.
Wilson, Ian A.
author_facet Irimia, Adriana
Serra, Andreia M.
Sarkar, Anita
Jacak, Ronald
Kalyuzhniy, Oleksandr
Sok, Devin
Saye-Francisco, Karen L.
Schiffner, Torben
Tingle, Ryan
Kubitz, Michael
Adachi, Yumiko
Stanfield, Robyn L.
Deller, Marc C.
Burton, Dennis R.
Schief, William R.
Wilson, Ian A.
author_sort Irimia, Adriana
collection PubMed
description Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity. Here we report x-ray structures of lipid complexes with 10E8 and a scaffolded MPER construct and mutagenesis studies that provide evidence that the 10E8 epitope is composed of both MPER and lipid. 10E8 engages lipids through a specific lipid head group interaction site and a basic and polar surface on the light chain. In the model that we constructed, the MPER would then be essentially perpendicular to the virion membrane during 10E8 neutralization of HIV-1. As the viral membrane likely also plays a role in selecting for the germline antibody as well as size and residue composition of MPER antibody complementarity determining regions, the identification of lipid interaction sites and the MPER orientation with regard to the viral membrane surface during 10E8 engagement can be of great utility for immunogen and therapeutic design.
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spelling pubmed-53388322017-03-09 Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design Irimia, Adriana Serra, Andreia M. Sarkar, Anita Jacak, Ronald Kalyuzhniy, Oleksandr Sok, Devin Saye-Francisco, Karen L. Schiffner, Torben Tingle, Ryan Kubitz, Michael Adachi, Yumiko Stanfield, Robyn L. Deller, Marc C. Burton, Dennis R. Schief, William R. Wilson, Ian A. PLoS Pathog Research Article Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity. Here we report x-ray structures of lipid complexes with 10E8 and a scaffolded MPER construct and mutagenesis studies that provide evidence that the 10E8 epitope is composed of both MPER and lipid. 10E8 engages lipids through a specific lipid head group interaction site and a basic and polar surface on the light chain. In the model that we constructed, the MPER would then be essentially perpendicular to the virion membrane during 10E8 neutralization of HIV-1. As the viral membrane likely also plays a role in selecting for the germline antibody as well as size and residue composition of MPER antibody complementarity determining regions, the identification of lipid interaction sites and the MPER orientation with regard to the viral membrane surface during 10E8 engagement can be of great utility for immunogen and therapeutic design. Public Library of Science 2017-02-22 /pmc/articles/PMC5338832/ /pubmed/28225819 http://dx.doi.org/10.1371/journal.ppat.1006212 Text en © 2017 Irimia et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Irimia, Adriana
Serra, Andreia M.
Sarkar, Anita
Jacak, Ronald
Kalyuzhniy, Oleksandr
Sok, Devin
Saye-Francisco, Karen L.
Schiffner, Torben
Tingle, Ryan
Kubitz, Michael
Adachi, Yumiko
Stanfield, Robyn L.
Deller, Marc C.
Burton, Dennis R.
Schief, William R.
Wilson, Ian A.
Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design
title Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design
title_full Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design
title_fullStr Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design
title_full_unstemmed Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design
title_short Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design
title_sort lipid interactions and angle of approach to the hiv-1 viral membrane of broadly neutralizing antibody 10e8: insights for vaccine and therapeutic design
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338832/
https://www.ncbi.nlm.nih.gov/pubmed/28225819
http://dx.doi.org/10.1371/journal.ppat.1006212
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