Title | Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Medina-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 PJohan, Moore JP, Nemazee D, Nussenzweig MC, Wilson IA, Sanders RW |
Journal | J Exp Med |
Volume | 214 |
Issue | 9 |
Pagination | 2573-2590 |
Date Published | 2017 Sep 04 |
ISSN | 1540-9538 |
Keywords | Animals, Antibodies, Neutralizing, Crystallography, X-Ray, Gene Knock-In Techniques, HEK293 Cells, HIV Envelope Protein gp160, HIV-1, Humans, Mice, Protein Multimerization, Protein Structure, Tertiary |
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. |
DOI | 10.1084/jem.20161160 |
Alternate Journal | J. Exp. Med. |
PubMed ID | 28847869 |
PubMed Central ID | PMC5584115 |
Grant List | P01 AI110657 / AI / NIAID NIH HHS / United States R01 AI073148 / AI / NIAID NIH HHS / United States R01 AI128836 / AI / NIAID NIH HHS / United States UM1 AI100663 / AI / NIAID NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm