Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

Max Medina-Ramírez; Fernando Garces; Amelia Escolano; Patrick Skog; Steven W. de Taeye; Ivan Del Moral-Sanchez; Andrew T. McGuire; Anila Yasmeen; Anna Janina Behrens; Gabriel Ozorowski; Tom L.G.M. van den Kerkhof; Natalia T. Freund; Pia Dosenovic; Yuanzi Hua; Alexander D. Gitlin; Albert Cupo; Patricia van der Woude; Michael Golabek; Kwinten Sliepen; Tanya Blane; Neeltje Kootstra; Mariëlle J. van Breemen; Laura K. Pritchard; Robyn L. Stanfield; Max Crispin; Andrew B. Ward; Leonidas Stamatatos; Per Johan Klasse; John P. Moore; David Nemazee; Michel C. Nussenzweig; Ian A. Wilson; Rogier W. Sanders

doi:https://doi.org/10.1084/jem.20161160

Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

Max Medina-Ramírez, Fernando Garces, Amelia Escolano, Patrick Skog, Steven W. de Taeye, Ivan Del Moral-Sanchez, Andrew T. McGuire, Anila Yasmeen, Anna Janina Behrens, Gabriel Ozorowski, Tom L.G.M. van den Kerkhof, Natalia T. Freund, Pia Dosenovic, Yuanzi Hua, Alexander D. Gitlin, Albert Cupo, Patricia van der Woude, Michael Golabek, Kwinten Sliepen, Tanya BlaneNeeltje Kootstra, Mariëlle J. van Breemen, Laura K. Pritchard, Robyn L. Stanfield, Max Crispin, Andrew B. Ward, Leonidas Stamatatos, Per Johan Klasse, John P. Moore, David Nemazee, Michel C. Nussenzweig, Ian A. Wilson, Rogier W. Sanders

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

Abstract

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOS IP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOS IP.v4.1- GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.

Original language	English
Pages (from-to)	2573-2590
Number of pages	18
Journal	Journal of Experimental Medicine
Volume	214
Issue number	9
DOIs	https://doi.org/10.1084/jem.20161160
State	Published - 2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1084/jem.20161160

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Medina-Ramírez, M., Garces, F., Escolano, A., Skog, P., de Taeye, S. W., Del Moral-Sanchez, I., McGuire, A. T., Yasmeen, A., Behrens, A. J., Ozorowski, G., van den Kerkhof, T. L. G. M., Freund, N. T., Dosenovic, P., Hua, Y., Gitlin, A. D., Cupo, A., van der Woude, P., Golabek, M., Sliepen, K., ... Sanders, R. W. (2017). Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. Journal of Experimental Medicine, 214(9), 2573-2590. https://doi.org/10.1084/jem.20161160

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title = "Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo",

abstract = "Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOS IP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOS IP.v4.1- GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-{\AA} resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.",

author = "Max Medina-Ram{\'i}rez and Fernando Garces and Amelia Escolano and Patrick Skog and {de Taeye}, {Steven W.} and {Del Moral-Sanchez}, Ivan and McGuire, {Andrew T.} and Anila Yasmeen and Behrens, {Anna Janina} and Gabriel Ozorowski and {van den Kerkhof}, {Tom L.G.M.} and Freund, {Natalia T.} and Pia Dosenovic and Yuanzi Hua and Gitlin, {Alexander D.} and Albert Cupo and {van der Woude}, Patricia and Michael Golabek and Kwinten Sliepen and Tanya Blane and Neeltje Kootstra and {van Breemen}, {Mari{\"e}lle J.} and Pritchard, {Laura K.} and Stanfield, {Robyn L.} and Max Crispin and Ward, {Andrew B.} and Leonidas Stamatatos and Klasse, {Per Johan} and Moore, {John P.} and David Nemazee and Nussenzweig, {Michel C.} and Wilson, {Ian A.} and Sanders, {Rogier W.}",

note = "Publisher Copyright: {\textcopyright} 2017 Medina-Ram{\'i}rez et al.",

year = "2017",

doi = "https://doi.org/10.1084/jem.20161160",

language = "الإنجليزيّة",

volume = "214",

pages = "2573--2590",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

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Medina-Ramírez, M, Garces, F, Escolano, A, Skog, P, de Taeye, SW, Del Moral-Sanchez, I, McGuire, AT, Yasmeen, A, Behrens, AJ, Ozorowski, G, van den Kerkhof, TLGM, Freund, NT, Dosenovic, P, Hua, Y, Gitlin, AD, Cupo, A, van der Woude, P, Golabek, M, Sliepen, K, Blane, T, Kootstra, N, van Breemen, MJ, Pritchard, LK, Stanfield, RL, Crispin, M, Ward, AB, Stamatatos, L, Klasse, PJ, Moore, JP, Nemazee, D, Nussenzweig, MC, Wilson, IA & Sanders, RW 2017, 'Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo', Journal of Experimental Medicine, vol. 214, no. 9, pp. 2573-2590. https://doi.org/10.1084/jem.20161160

TY - JOUR

T1 - Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

AU - Medina-Ramírez, Max

AU - Garces, Fernando

AU - Escolano, Amelia

AU - Skog, Patrick

AU - de Taeye, Steven W.

AU - Del Moral-Sanchez, Ivan

AU - McGuire, Andrew T.

AU - Yasmeen, Anila

AU - Behrens, Anna Janina

AU - Ozorowski, Gabriel

AU - van den Kerkhof, Tom L.G.M.

AU - Freund, Natalia T.

AU - Dosenovic, Pia

AU - Hua, Yuanzi

AU - Gitlin, Alexander D.

AU - Cupo, Albert

AU - van der Woude, Patricia

AU - Golabek, Michael

AU - Sliepen, Kwinten

AU - Blane, Tanya

AU - Kootstra, Neeltje

AU - van Breemen, Mariëlle J.

AU - Pritchard, Laura K.

AU - Stanfield, Robyn L.

AU - Crispin, Max

AU - Ward, Andrew B.

AU - Stamatatos, Leonidas

AU - Klasse, Per Johan

AU - Moore, John P.

AU - Nemazee, David

AU - Nussenzweig, Michel C.

AU - Wilson, Ian A.

AU - Sanders, Rogier W.

PY - 2017

Y1 - 2017

N2 - Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOS IP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOS IP.v4.1- GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.

AB - Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOS IP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOS IP.v4.1- GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.

UR - http://www.scopus.com/inward/record.url?scp=85028886518&partnerID=8YFLogxK

U2 - https://doi.org/10.1084/jem.20161160

DO - https://doi.org/10.1084/jem.20161160

M3 - مقالة

SN - 0022-1007

VL - 214

SP - 2573

EP - 2590

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 9

ER -

Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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