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

作者：Medina Ramirez Max; Garces Fernando; Escolano Amelia; Skog Patrick; de Taeye Steven W; Del Moral Sanchez Ivan; McGuire Andrew T; Yasmeen Anila; Behrens Anna Janina; Ozorowski Gabriel; van den Kerkhof Tom L G M; Freund Natalia T; Dosenovic Pia; Hua Yuanzi; Gitlin Alexander D; Cupo Albert; van der Woude Patricia; Golabek Michael; Sliepen Kwinten; Blane Tanya; Kootstra Neeltje; van Breemen Marielle J; Pritchard Laura K; Stanfield Robyn L; Crispin Max

来源：Journal of Experimental Medicine, 2017, 214(9): 2573-2590.

DOI：10.1084/jem.20161160

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. v4.1GT1 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-angstrom resolution in complex with neutralizing antibodies 35022 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.

• 出版日期2017-9