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Cell. 2019 Aug 8;178(4):1004-1015.e14. doi: 10.1016/j.cell.2019.07.020.

Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization.

Author information

1
La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
2
University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX, USA.
3
Zalgen Labs, Germantown, MD, USA.
4
Department of Pediatrics, School of Medicine, Tulane University, New Orleans, LA, USA.
5
Zalgen Labs, Germantown, MD, USA; Department of Microbiology and Immunology, Tulane University, New Orleans, LA, USA.
6
La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: erica@lji.org.

Abstract

Lassa virus (LASV) causes hemorrhagic fever and is endemic in West Africa. Protective antibody responses primarily target the LASV surface glycoprotein (GPC), and GPC-B competition group antibodies often show potent neutralizing activity in humans. However, which features confer potent and broadly neutralizing antibody responses is unclear. Here, we compared three crystal structures of LASV GPC complexed with GPC-B antibodies of varying neutralization potency. Each GPC-B antibody recognized an overlapping epitope involved in binding of two adjacent GPC monomers and preserved the prefusion trimeric conformation. Differences among GPC-antibody interactions highlighted specific residues that enhance neutralization. Using structure-guided amino acid substitutions, we increased the neutralization potency and breadth of these antibodies to include all major LASV lineages. The ability to define antibody residues that allow potent and broad neutralizing activity, together with findings from analyses of inferred germline precursors, is critical to develop potent therapeutics and for vaccine design and assessment.

KEYWORDS:

Lassa virus; antibody; arenavirus; germline; neutralization; protein engineering; structural biology

PMID:
31398326
DOI:
10.1016/j.cell.2019.07.020

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