Immunogenicity of stabilized HIV-1 envelope trimers with reduced exposure of non-neutralizing epitopes

de Taeye, Steven W., Ozorowski, Gabriel, Torrents de la Peña, Alba, Guttman, Miklos, Julien, Jean Philippe, van den Kerkhof, Tom L.G.M., Burger, Judith A., Pritchard, Laura K., Pugach, Pavel, Yasmeen, Anila, Crampton, Jordan, Hu, Joyce, Bontjer, Ilja, Torres, Jonathan L., Arendt, Heather, Destefano, Joanne, Koff, Wayne C., Schuitemaker, Hanneke, Eggink, Dirk, Berkhout, Ben, Dean, Hansi, Labranche, Celia, Crotty, Shane, Crispin, Max, Montefiori, David C., Klasse, P. J., Lee, Kelly K., Moore, John P., Wilson, Ian A., Ward, Andrew B. and Sanders, Rogier W. (2015) Immunogenicity of stabilized HIV-1 envelope trimers with reduced exposure of non-neutralizing epitopes. Cell, 163 (7), 1702-1715. (doi:10.1016/j.cell.2015.11.056).

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.

This record has no associated files available for download.

Contributors

Author: Max Crispin

Download statistics