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Nat Commun. 2019 Nov 26;10(1):5389. doi: 10.1038/s41467-019-12973-1.

An MPER antibody neutralizes HIV-1 using germline features shared among donors.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA.
2
CTK Biotech, Inc., 3855 Stowe Drive, Poway, California, 92064, USA.
3
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA.
4
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, California, 92037, USA.
5
Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, California, 92037, USA.
6
International AIDS Vaccine Initiative, New York, New York, 10004, USA.
7
Department of Medicine, University of California, San Diego, California, 92093, USA.
8
Departments of Medicine, Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
9
Institut de Biologie Structurale, Université Grenoble Alpes, Commissariat a l'Energie Atomique, Centre National de Recherche Scientifique and Centre Hospitalier Universitaire Grenoble Alpes, 38044, Grenoble, France.
10
Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachussetts, 02114, USA.
11
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
12
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA. jiang@scripps.edu.
13
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA. jiang@scripps.edu.
14
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu.
15
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu.
16
Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu.
17
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu.
18
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA. zwick@scripps.edu.

Abstract

The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. Here we describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. A recombinant sublineage variant pan-neutralizes a 130-isolate panel at 1.4 μg/ml (IC50). Notably, a germline revertant with mature CDR3s neutralizes 12% of viruses and still binds MPER after DJ reversion. Crystal structures of lipid-bound PGZL1 variants and cryo-EM reconstruction of an Env-PGZL1 complex reveal how these antibodies recognize MPER and viral membrane. Discovery of common genetic and structural elements among MPER antibodies from different patients suggests that such antibodies could be elicited using carefully designed immunogens.

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