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

Medina-Ramírez, 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, Mariëlle J.; Pritchard, Laura K.; Stanfield, Robyn L.; Crispin, Max; Ward, Andrew B.; Stamatatos, Leonidas; Klasse, Per Johan; Moore, John P.; Nemazee, David; Nussenzweig, Michel C.; Wilson, Ian A.; Sanders, Rogier W.

doi:10.1084/jem.20161160

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

Journal Article · Mon Aug 28 00:00:00 EDT 2017 · Journal of Experimental Medicine

DOI:https://doi.org/10.1084/jem.20161160· OSTI ID:1377638

; Garces, Fernando; Escolano, Amelia; ; de Taeye, Steven W.; Del Moral-Sanchez, Ivan; ; ; ; ; van den Kerkhof, Tom L. G. M.; Freund, Natalia T.; Dosenovic, Pia; Hua, Yuanzi; Gitlin, Alexander D.; Cupo, Albert; van der Woude, Patricia; ; Sliepen, Kwinten; more »

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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1377638

Alternate ID(s):: OSTI ID: 1499793

Journal Information:: Journal of Experimental Medicine, Journal Name: Journal of Experimental Medicine Journal Issue: 9 Vol. 214; ISSN 0022-1007

Publisher:: Rockefeller University PressCopyright Statement

Country of Publication:: United States

Language:: English

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