@article{1f8be8a9f8ac4fde9c3e87b46f9c0366,
title = "Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization",
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.",
keywords = "Lassa virus, antibody, arenavirus, germline, neutralization, protein engineering, structural biology",
author = "Hastie, {Kathryn M.} and Cross, {Robert W.} and Harkins, {Stephanie S.} and Zandonatti, {Michelle A.} and Koval, {Anatoliy P.} and Heinrich, {Megan L.} and Rowland, {Megan M.} and Robinson, {James E.} and Geisbert, {Thomas W.} and Garry, {Robert F.} and Branco, {Luis M.} and Saphire, {Erica Ollmann}",
note = "Funding Information: The authors wish to acknowledge Tierra Buck and Dipti Parekh for technical assistance. Data for the LASV GP-Fab 18.5C structure were collected on beamline 12-2 of the Stanford Synchrotron Radiation Lightsource. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, and Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health and National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Data for the LASV GP-Fab 18.5C structure were collected on beamlines 23-ID-B and 23-ID-D of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This work was supported by the Viral Hemorrhagic Fever Consortium (VHFC), the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC), US National Institutes of Health (NIH/NIAID) Center of Excellence in Translational Research (CETR) grants 1U19 AI109762 (E.O.S. J.E.R. and R.F.G.) and R01 AI132244 (R.F.G. L.M.B. and E.O.S.), and an Investigators in Pathogenesis of Infectious Diseases award from the Burroughs Wellcome Fund (E.O.S.). This is manuscript # 29659 from The Scripps Research Institute. Conceptualization, K.M.H and E.O.S.; Investigation, K.M.H. R.W.C. and S.S.H.; Resources, K.M.H. R.W.C. S.S.H. M.A.Z. A.P.K. M.L.H. M.M.R. J.E.R. L.M.B. and R.F.G.; Writing – Original Draft, K.M.H.; Writing – Review & Editing, K.M.H. R.W.C. J.E.R. L.M.B. R.F.G, T.W.C. and E.O.S.; Funding Acquisition, L.M.B. R.F.G. T.W.C. and E.O.S; Supervision: E.O.S. L.M.B. and R.F.G. are co-founders of Zalgen Labs. L.M.B. receives compensation from Zalgen Labs. R.F.G. does not receive compensation from Zalgen Labs. M.L.H. M.M.R. and A.P.K. are employed by Zalgen Labs and receive compensation from the company. The remaining authors declare no competing interests. Funding Information: The authors wish to acknowledge Tierra Buck and Dipti Parekh for technical assistance. Data for the LASV GP-Fab 18.5C structure were collected on beamline 12-2 of the Stanford Synchrotron Radiation Lightsource. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, and Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health and National Institute of General Medical Sciences (including P41GM103393 ) . The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Data for the LASV GP-Fab 18.5C structure were collected on beamlines 23-ID-B and 23-ID-D of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This work was supported by the Viral Hemorrhagic Fever Consortium (VHFC), the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC), US National Institutes of Health (NIH/NIAID) Center of Excellence in Translational Research (CETR) grants 1U19 AI109762 (E.O.S., J.E.R., and R.F.G.) and R01 AI132244 (R.F.G., L.M.B. and E.O.S.), and an Investigators in Pathogenesis of Infectious Diseases award from the Burroughs Wellcome Fund (E.O.S.). This is manuscript # 29659 from The Scripps Research Institute. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = aug,
day = "8",
doi = "10.1016/j.cell.2019.07.020",
language = "English (US)",
volume = "178",
pages = "1004--1015.e14",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}