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

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.
Authors:
ORCiD logo [1] ;  [2] ;  [3] ; ORCiD logo [4] ;  [1] ;  [1] ; ORCiD logo [5] ; ORCiD logo [6] ; ORCiD logo [7] ; ORCiD logo [2] ;  [8] ;  [3] ;  [2] ;  [2] ;  [3] ;  [6] ;  [1] ; ORCiD logo [6] ;  [1] ; ORCiD logo [4] more »; ORCiD logo [9] ;  [1] ;  [7] ; ORCiD logo [2] ;  [7] ;  [2] ;  [5] ; ORCiD logo [6] ; ORCiD logo [6] ; ORCiD logo [4] ; ORCiD logo [10] ;  [2] ;  [11] « less
  1. Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  2. Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA
  3. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY
  4. Department of Immunology and Microbiology, Scripps CHAVI-ID, The Scripps Research Institute, La Jolla, CA
  5. Seattle Biomedical Research Institute, Seattle, WA
  6. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY
  7. Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, England, UK
  8. Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  9. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  10. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, Howard Hughes Medical Institute, The Rockefeller University, New York, NY
  11. Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY
Publication Date:
Grant/Contract Number:
AC02-06CH11357
Type:
Published Article
Journal Name:
Journal of Experimental Medicine
Additional Journal Information:
Journal Name: Journal of Experimental Medicine Journal Volume: 214 Journal Issue: 9; Journal ID: ISSN 0022-1007
Publisher:
Rockefeller University Press
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
OSTI Identifier:
1377638

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., and Sanders, Rogier W.. Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. United States: N. p., Web. doi:10.1084/jem.20161160.
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.. Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. United States. doi:10.1084/jem.20161160.
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., and Sanders, Rogier W.. 2017. "Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo". United States. doi:10.1084/jem.20161160.
@article{osti_1377638,
title = {Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo},
author = {Medina-Ramírez, Max and Garces, Fernando and Escolano, Amelia and Skog, Patrick and de Taeye, Steven W. and Del Moral-Sanchez, Ivan and McGuire, Andrew T. and Yasmeen, Anila and Behrens, Anna-Janina and Ozorowski, Gabriel and van den Kerkhof, Tom L. G. M. and Freund, Natalia T. and Dosenovic, Pia and Hua, Yuanzi and Gitlin, Alexander D. and Cupo, Albert and van der Woude, Patricia and Golabek, Michael and Sliepen, Kwinten and Blane, Tanya and Kootstra, Neeltje and van Breemen, Mariëlle J. and Pritchard, Laura K. and Stanfield, Robyn L. and Crispin, Max and Ward, Andrew B. and Stamatatos, Leonidas and Klasse, Per Johan and Moore, John P. and Nemazee, David and Nussenzweig, Michel C. and Wilson, Ian A. and Sanders, Rogier W.},
abstractNote = {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},
journal = {Journal of Experimental Medicine},
number = 9,
volume = 214,
place = {United States},
year = {2017},
month = {8}
}

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A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies
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Coot model-building tools for molecular graphics
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