期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 9, 页码 2573-2590出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161160
关键词
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资金
- Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- Department of Energy Office of Science [DE-AC02-06CH11357]
- Consejo Nacional de Ciencia y Tecnologia of Mexico
- Netherlands Organization for Scientific Research [917.11.314]
- European Research Council [ERC-StG-2011-280829-SHEV]
- Aids Fonds Netherlands [20160192]
- National Institutes of Health grant [P01 AI110657]
- International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium [SFP1849]
- Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery [UM1 AI100663]
- National Institutes of Health [R01 AI073148]
- Collaboration for AIDS Vaccine Discovery [0PP1111923, 0PP1132237]
- Bill and Melinda Gates Foundation [0PP1115782]
- European Union Horizon research and innovation program [681137]
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.
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