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

Kathryn M. Hastie, Robert Cross, Stephanie S. Harkins, Michelle A. Zandonatti, Anatoliy P. Koval, Megan L. Heinrich, Megan M. Rowland, James E. Robinson, Thomas Geisbert, Robert F. Garry, Luis M. Branco, Erica Ollmann Saphire

Research output: Contribution to journalArticle

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. Structural studies identify antibody features that provide potent neutralization against Lassa virus.

Original languageEnglish (US)
Pages (from-to)1004-1015.e14
JournalCell
Volume178
Issue number4
DOIs
StatePublished - Aug 8 2019

Fingerprint

Lassa virus
Viruses
Antibodies
Antibody Formation
Western Africa
Membrane Glycoproteins
Amino Acid Substitution
Neutralizing Antibodies
Human Activities
Epitopes
Fever
Vaccines
Conformations
Substitution reactions
Monomers
Crystal structure
Amino Acids

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hastie, K. M., Cross, R., Harkins, S. S., Zandonatti, M. A., Koval, A. P., Heinrich, M. L., ... Saphire, E. O. (2019). Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization. Cell, 178(4), 1004-1015.e14. https://doi.org/10.1016/j.cell.2019.07.020

Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization. / Hastie, Kathryn M.; Cross, Robert; Harkins, Stephanie S.; Zandonatti, Michelle A.; Koval, Anatoliy P.; Heinrich, Megan L.; Rowland, Megan M.; Robinson, James E.; Geisbert, Thomas; Garry, Robert F.; Branco, Luis M.; Saphire, Erica Ollmann.

In: Cell, Vol. 178, No. 4, 08.08.2019, p. 1004-1015.e14.

Research output: Contribution to journalArticle

Hastie, KM, Cross, R, Harkins, SS, Zandonatti, MA, Koval, AP, Heinrich, ML, Rowland, MM, Robinson, JE, Geisbert, T, Garry, RF, Branco, LM & Saphire, EO 2019, 'Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization', Cell, vol. 178, no. 4, pp. 1004-1015.e14. https://doi.org/10.1016/j.cell.2019.07.020
Hastie, Kathryn M. ; Cross, Robert ; Harkins, Stephanie S. ; Zandonatti, Michelle A. ; Koval, Anatoliy P. ; Heinrich, Megan L. ; Rowland, Megan M. ; Robinson, James E. ; Geisbert, Thomas ; Garry, Robert F. ; Branco, Luis M. ; Saphire, Erica Ollmann. / Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization. In: Cell. 2019 ; Vol. 178, No. 4. pp. 1004-1015.e14.
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