Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Steven W. de Taeye; Gabriel Ozorowski; Alba Torrents de la Peña; Miklos Guttman; Jean-Philippe Julien; Tom L. G. M. van den Kerkhof; Judith A. Burger; Laura K. Pritchard; Pavel Pugach; Anila Yasmeen; Jordan Crampton; Joyce Hu; Ilja Bontjer; Jonathan L. Torres; Heather Arendt; Joanne DeStefano; Wayne C. Koff; Hanneke Schuitemaker; Dirk Eggink; Ben Berkhout; Hansi Dean; Celia Labranche; Shane Crotty; Max Crispin; David C. Montefiori; P. J. Klasse; Kelly K. Lee; John P. Moore; Ian A. Wilson; Andrew B. Ward; Rogier W. Sanders

doi:10.1016/j.cell.2015.11.056

Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Steven W. de Taeye
, Gabriel Ozorowski
, Alba Torrents de la Peña
, Miklos Guttman
, Jean-Philippe Julien
, Tom L. G. M. van den Kerkhof
, Judith A. Burger
, Laura K. Pritchard
, Pavel Pugach
, Anila Yasmeen
, Jordan Crampton
, Joyce Hu
, Ilja Bontjer
, Jonathan L. Torres
, Heather Arendt
, Joanne DeStefano
, Wayne C. Koff
, Hanneke Schuitemaker
, Dirk Eggink
, Ben Berkhout

Hansi Dean, Celia Labranche, Shane Crotty, Max Crispin, David C. Montefiori, P. J. Klasse, Kelly K. Lee, John P. Moore, Ian A. Wilson, Andrew B. Ward, Rogier W. Sanders

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

Abstract

The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs

Original language	English
Pages (from-to)	1702-1715
Journal	Cell
Volume	163
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2015.11.056
Publication status	Published - 2015

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10.1016/j.cell.2015.11.056

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de Taeye, S. W., Ozorowski, G., Torrents de la Peña, A., Guttman, M., Julien, J.-P., van den Kerkhof, T. L. G. M., Burger, J. A., Pritchard, L. K., Pugach, P., Yasmeen, A., Crampton, J., Hu, J., Bontjer, I., Torres, J. L., Arendt, H., DeStefano, J., Koff, W. C., Schuitemaker, H., Eggink, D., ... Sanders, R. W. (2015). Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes. Cell, 163(7), 1702-1715. https://doi.org/10.1016/j.cell.2015.11.056

@article{78adc9216fc942cfbdd24ef182ffbc6d,

title = "Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes",

abstract = "The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs",

author = "\{de Taeye\}, \{Steven W.\} and Gabriel Ozorowski and \{Torrents de la Pe{\~n}a\}, Alba and Miklos Guttman and Jean-Philippe Julien and \{van den Kerkhof\}, \{Tom L. G. M.\} and Burger, \{Judith A.\} and Pritchard, \{Laura K.\} and Pavel Pugach and Anila Yasmeen and Jordan Crampton and Joyce Hu and Ilja Bontjer and Torres, \{Jonathan L.\} and Heather Arendt and Joanne DeStefano and Koff, \{Wayne C.\} and Hanneke Schuitemaker and Dirk Eggink and Ben Berkhout and Hansi Dean and Celia Labranche and Shane Crotty and Max Crispin and Montefiori, \{David C.\} and Klasse, \{P. J.\} and Lee, \{Kelly K.\} and Moore, \{John P.\} and Wilson, \{Ian A.\} and Ward, \{Andrew B.\} and Sanders, \{Rogier W.\}",

year = "2015",

doi = "10.1016/j.cell.2015.11.056",

language = "English",

volume = "163",

pages = "1702--1715",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "7",

}

de Taeye, SW, Ozorowski, G, Torrents de la Peña, A, Guttman, M, Julien, J-P, van den Kerkhof, TLGM, Burger, JA, Pritchard, LK, Pugach, P, Yasmeen, A, Crampton, J, Hu, J, Bontjer, I, Torres, JL, Arendt, H, DeStefano, J, Koff, WC, Schuitemaker, H, Eggink, D , Berkhout, B, Dean, H, Labranche, C, Crotty, S, Crispin, M, Montefiori, DC, Klasse, PJ, Lee, KK, Moore, JP, Wilson, IA, Ward, AB & Sanders, RW 2015, 'Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes', Cell, vol. 163, no. 7, pp. 1702-1715. https://doi.org/10.1016/j.cell.2015.11.056

TY - JOUR

T1 - Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

AU - de Taeye, Steven W.

AU - Ozorowski, Gabriel

AU - Torrents de la Peña, Alba

AU - Guttman, Miklos

AU - Julien, Jean-Philippe

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

AU - Burger, Judith A.

AU - Pritchard, Laura K.

AU - Pugach, Pavel

AU - Yasmeen, Anila

AU - Crampton, Jordan

AU - Hu, Joyce

AU - Bontjer, Ilja

AU - Torres, Jonathan L.

AU - Arendt, Heather

AU - DeStefano, Joanne

AU - Koff, Wayne C.

AU - Schuitemaker, Hanneke

AU - Eggink, Dirk

AU - Berkhout, Ben

AU - Dean, Hansi

AU - Labranche, Celia

AU - Crotty, Shane

AU - Crispin, Max

AU - Montefiori, David C.

AU - Klasse, P. J.

AU - Lee, Kelly K.

AU - Moore, John P.

AU - Wilson, Ian A.

AU - Ward, Andrew B.

AU - Sanders, Rogier W.

PY - 2015

Y1 - 2015

N2 - The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs

AB - The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs

U2 - 10.1016/j.cell.2015.11.056

DO - 10.1016/j.cell.2015.11.056

M3 - Article

C2 - 26687358

SN - 0092-8674

VL - 163

SP - 1702

EP - 1715

JO - Cell

JF - Cell

IS - 7

ER -

Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Abstract

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