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An MPER antibody neutralizes HIV-1 using germline features shared among donors.
Nat Commun. 2019 11 26; 10(1):5389.NC

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+Show Affiliations

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA. CTK Biotech, Inc., 3855 Stowe Drive, Poway, California, 92064, USA.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.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.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 Institute, La Jolla, California, 92037, USA. International AIDS Vaccine Initiative, New York, New York, 10004, USA.Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA.Department of Medicine, University of California, San Diego, California, 92093, USA.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA. Departments of Medicine, Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.No affiliation info availableDepartment 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 Institute, La Jolla, California, 92037, USA. International AIDS Vaccine Initiative, New York, New York, 10004, USA. 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 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 Institute, La Jolla, California, 92037, USA. Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, California, 92037, USA. Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachussetts, 02114, USA.Department of Medicine, University of California, San Diego, California, 92093, USA. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.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.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA. jiang@scripps.edu. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA. jiang@scripps.edu.Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu. 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. Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037, USA. wilson@scripps.edu.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, 92037, USA. zwick@scripps.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

31772165

Citation

Zhang, Lei, et al. "An MPER Antibody Neutralizes HIV-1 Using Germline Features Shared Among Donors." Nature Communications, vol. 10, no. 1, 2019, p. 5389.
Zhang L, Irimia A, He L, et al. An MPER antibody neutralizes HIV-1 using germline features shared among donors. Nat Commun. 2019;10(1):5389.
Zhang, L., Irimia, A., He, L., Landais, E., Rantalainen, K., Leaman, D. P., Vollbrecht, T., Stano, A., Sands, D. I., Kim, A. S., Poignard, P., Burton, D. R., Murrell, B., Ward, A. B., Zhu, J., Wilson, I. A., & Zwick, M. B. (2019). An MPER antibody neutralizes HIV-1 using germline features shared among donors. Nature Communications, 10(1), 5389. https://doi.org/10.1038/s41467-019-12973-1
Zhang L, et al. An MPER Antibody Neutralizes HIV-1 Using Germline Features Shared Among Donors. Nat Commun. 2019 11 26;10(1):5389. PubMed PMID: 31772165.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An MPER antibody neutralizes HIV-1 using germline features shared among donors. AU - Zhang,Lei, AU - Irimia,Adriana, AU - He,Lingling, AU - Landais,Elise, AU - Rantalainen,Kimmo, AU - Leaman,Daniel P, AU - Vollbrecht,Thomas, AU - Stano,Armando, AU - Sands,Daniel I, AU - Kim,Arthur S, AU - ,, AU - Poignard,Pascal, AU - Burton,Dennis R, AU - Murrell,Ben, AU - Ward,Andrew B, AU - Zhu,Jiang, AU - Wilson,Ian A, AU - Zwick,Michael B, Y1 - 2019/11/26/ PY - 2019/03/22/received PY - 2019/10/11/accepted PY - 2019/11/28/entrez PY - 2019/11/28/pubmed PY - 2020/4/14/medline SP - 5389 EP - 5389 JF - Nature communications JO - Nat Commun VL - 10 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/31772165/An_MPER_antibody_neutralizes_HIV-1_using_germline_features_shared_among_donors L2 - http://dx.doi.org/10.1038/s41467-019-12973-1 DB - PRIME DP - Unbound Medicine ER -