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

Lei Zhang, Adriana Irimia, Lingling He, Elise Landais, Kimmo Rantalainen, Daniel P. Leaman, Thomas Vollbrecht, Armando Stano, Daniel I. Sands, Arthur S. Kim, Pascal Poignard, Dennis R. Burton, Ben Murrell, Andrew B. Ward, Jiang Zhu (), Ian A. Wilson () and Michael B. Zwick ()
Additional contact information
Lei Zhang: The Scripps Research Institute
Adriana Irimia: The Scripps Research Institute
Lingling He: The Scripps Research Institute
Elise Landais: The Scripps Research Institute
Kimmo Rantalainen: The Scripps Research Institute
Daniel P. Leaman: The Scripps Research Institute
Thomas Vollbrecht: University of California
Armando Stano: The Scripps Research Institute
Daniel I. Sands: The Scripps Research Institute
Arthur S. Kim: The Scripps Research Institute
Pascal Poignard: The Scripps Research Institute
Dennis R. Burton: The Scripps Research Institute
Ben Murrell: University of California
Andrew B. Ward: The Scripps Research Institute
Jiang Zhu: The Scripps Research Institute
Ian A. Wilson: The Scripps Research Institute
Michael B. Zwick: The Scripps Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12973-1

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