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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];  [1];  [1];  [2];  [1];  [1]; ORCiD logo [3];  [1]; ORCiD logo [1]; ORCiD logo [1];  [2]; ORCiD logo [4];  [5]; ORCiD logo [1];  [1]; ORCiD logo [1];  [1]
  1. The Scripps Research Inst., La Jolla, CA (United States)
  2. The Scripps Research Inst., La Jolla, CA (United States); International AIDS Vaccine Initiative, New York, NY (United States)
  3. Univ. of California, San Diego, CA (United States)
  4. The Scripps Research Inst., La Jolla, CA (United States); MIT and Harvard, Cambridge, MA (United States). Ragon Institute of Massachusetts General Hospital
  5. Univ. of California, San Diego, CA (United States); Karolinska Institutet, Stockholm (Sweden). Department of Microbiology, Tumor and Cell Biology
Publication Date:
Research Org.:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
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); 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; National Institute of General Medical Sciences (NIGMS)
Contributing Org.:
IAVI Protocol G Investigators
OSTI Identifier:
1624211
Grant/Contract Number:  
AC02-76SF00515; AI129698; AI140844
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; Antibodies; HIV infections; Vaccines; X-ray crystallography

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. doi: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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