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

TitleDesign and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo.
Publication TypeJournal Article
Year of Publication2017
AuthorsMedina-Ramírez M, Garces F, Escolano A, Skog P, de Taeye SW, Del Moral-Sanchez I, McGuire AT, Yasmeen A, Behrens A-J, 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 P J, Moore JP, Nemazee D, Nussenzweig MC, Wilson IA, Sanders RW
JournalJ Exp Med
Volume214
Issue9
Pagination2573-2590
Date Published09/04/2017
ISSN1540-9538
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 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.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.

DOI10.1084/jem.20161160
Alternate JournalJ. Exp. Med.
PubMed ID28847869
PubMed Central IDPMC5584115
Grant ListP01 AI110657 / AI / NIAID NIH HHS / United States
R01 AI073148 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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