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

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.

Authors:
 [1];  [2];  [3];  [4];  [5];  [6]; ORCiD logo [7];  [6]; ORCiD logo [6]; ORCiD logo [8];  [9]; ORCiD logo [10];  [11]; ORCiD logo [12];  [13]; ORCiD logo [14];  [6]
  1. CTK Biotech, Inc., 3855 Stowe Drive, Poway, California, 92064, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA
  2. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, California, 92037, USA; Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, California, 92037, USA
  3. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA
  4. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Inst
  5. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA
  6. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, 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; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, 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; Department of Immunology and Micro
  10. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA; Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachussetts, 02114, USA
  11. Department of Medicine, University of California, San Diego, California, 92093, USA; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
  12. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, California, 92037, USA
  13. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA
  14. Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, California, 92037, USA Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037, USA
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Scripps CHACI-ID; Scripps CHAVD; HIV Vaccine Research and Design (HIVRAD); James B. Pendleton Charitable Trust; United States Agency for International Development (USAID), Ministry of Foreign Affairs of the Netherlands, Bill & Melinda Gates Foundation
Contributing Org.:
IAVI Protocol G Investigators
OSTI Identifier:
1624211
Grant/Contract Number:  
AC02-76SF00515; R01 AI114401; AI143563; UM1 AI100663; UM1 AI144462; P01 AI124337; AI129698; AI140844; CAVD OPP1084519; P41GM103393
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology - Other Topics

Citation Formats

Zhang, Lei, Irimia, Adriana, He, Lingling, Landais, Elise, Rantalainen, Kimmo, Leaman, Daniel P., Vollbrecht, Thomas, Stano, Armando, Sands, Daniel I., Kim, Arthur S., Poignard, Pascal, Burton, Dennis R., Murrell, Ben, Ward, Andrew B., Zhu, Jiang, Wilson, Ian A., and Zwick, Michael B.. An MPER antibody neutralizes HIV-1 using germline features shared among donors. United States: N. p., 2019. Web. https://doi.org/10.1038/s41467-019-12973-1.
Zhang, Lei, Irimia, Adriana, He, Lingling, Landais, Elise, Rantalainen, Kimmo, Leaman, Daniel P., Vollbrecht, Thomas, Stano, Armando, Sands, Daniel I., Kim, Arthur S., Poignard, Pascal, Burton, Dennis R., Murrell, Ben, Ward, Andrew B., Zhu, Jiang, Wilson, Ian A., & Zwick, Michael B.. An MPER antibody neutralizes HIV-1 using germline features shared among donors. United States. https://doi.org/10.1038/s41467-019-12973-1
Zhang, Lei, Irimia, Adriana, He, Lingling, Landais, Elise, Rantalainen, Kimmo, Leaman, Daniel P., Vollbrecht, Thomas, Stano, Armando, Sands, Daniel I., Kim, Arthur S., Poignard, Pascal, Burton, Dennis R., Murrell, Ben, Ward, Andrew B., Zhu, Jiang, Wilson, Ian A., and Zwick, Michael B.. Tue . "An MPER antibody neutralizes HIV-1 using germline features shared among donors". United States. https://doi.org/10.1038/s41467-019-12973-1. https://www.osti.gov/servlets/purl/1624211.
@article{osti_1624211,
title = {An MPER antibody neutralizes HIV-1 using germline features shared among donors},
author = {Zhang, Lei and Irimia, Adriana and He, Lingling and Landais, Elise and Rantalainen, Kimmo and Leaman, Daniel P. and Vollbrecht, Thomas and Stano, Armando and Sands, Daniel I. and Kim, Arthur S. and Poignard, Pascal and Burton, Dennis R. and Murrell, Ben and Ward, Andrew B. and Zhu, Jiang and Wilson, Ian A. and Zwick, Michael B.},
abstractNote = {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.},
doi = {10.1038/s41467-019-12973-1},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {11}
}

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