A protective monoclonal antibody targets a site of vulnerability on the surface of Rift Valley fever virus

Allen, E. R. et al. (2018) A protective monoclonal antibody targets a site of vulnerability on the surface of Rift Valley fever virus. Cell Reports, 25(13), 3750-3758.e4. (doi: 10.1016/j.celrep.2018.12.001) (PMID:30590046) (PMCID:PMC6315105)

Abstract

The Gn subcomponent of the Gn-Gc assembly that envelopes the human and animal pathogen, Rift Valley fever virus (RVFV), is a primary target of the neutralizing antibody response. To better understand the molecular basis for immune recognition, we raised a class of neutralizing monoclonal antibodies (nAbs) against RVFV Gn, which exhibited protective efficacy in a mouse infection model. Structural characterization revealed that these nAbs were directed to the membrane-distal domain of RVFV Gn and likely prevented virus entry into a host cell by blocking fusogenic rearrangements of the Gn-Gc lattice. Genome sequence analysis confirmed that this region of the RVFV Gn-Gc assembly was under selective pressure and constituted a site of vulnerability on the virion surface. These data provide a blueprint for the rational design of immunotherapeutics and vaccines capable of preventing RVFV infection and a model for understanding Ab-mediated neutralization of bunyaviruses more generally.

• Item Type: Articles
• Additional Information: T.A.B. and K.J.D. are supported by the Medical Research Council (MR/L009528/1, MR/K024426/1, and MR/N002091/1) and Wellcome (089026/Z/09/Z to T.A.B.). G.M.W. is supported through an Oak Foundation Fellowship. This study is published with the permission of the Director of the Kenya Medical Research Institute. O.G.P. was funded by the European Research Council under FP7/2007-2013/European Research Council grant agreement 614725-PATHPHYLODYN. S.H. and J.T.H. are supported by European Research Council under the European Union’s Horizon 2020 research and innovation program (649053). The Wellcome Centre for Human Genetics is supported by grant 203141/Z/16/Z. E.R.A. is the recipient of a PHE PhD studentship.
• Keywords: Rift Valley fever virus, antibody, antiviral, bunyavirus, immune response, neutralization, phlebovirus, structure, vaccine, virus-host interactions.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Elliott, Professor Richard and Elliott, Mrs Angela and Koudriakova, Elina and Brennan, Dr Benjamin
• Authors: Allen, E. R., Krumm, S. A., Raghwani, J., Halldorsson, S., Elliott, A., Graham, V. A., Koudriakova, E., Harlos, K., Wright, D., Warimwe, G. M., Brennan, B., Huiskonen, J. T., Dowall, S. D., Elliott, R. M., Pybus, O. G., Burton, D. R., Hewson, R., Doores, K. J., and Bowden, T. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Cell Reports 25(13): 3750-3758.e4
• Publisher Policy: Reproduced under a Creative Commons License