A protective monoclonal antibody targets a site of vulnerability on the surface of Rift Valley Fever Virus

DOI: 10.1016/j.celrep.2018.12.001

Authors: Elizabeth R. Allen (Wellcome Centre for Human Genetics, University of Oxford) , Stefanie A. Krumm (Kings College London) , Jayna Raghwani (University of Oxford) , Steinar Halldorsson (Wellcome Centre for Human Genetics, University of Oxford) , Angela Elliott (MRC-University of Glasgow Centre for Virus Research) , Victoria A. Graham (Public Health England) , Elina Koudriakova (MRC-University of Glasgow Centre for Virus Research) , Karl Harlos (Wellcome Centre for Human Genetics, University of Oxford) , Daniel Wright (The Jenner Institute, University of Oxford) , George M. Warimwe (University of Oxford; Kenya Medical Research Institute (KEMRI)) , Benjamin Brennan (MRC-University of Glasgow Centre for Virus Research) , Juha T. Huiskonen (Wellcome Centre for Human Genetics, University of Oxford) , Stuart D. Dowall (Public Health England) , Richard M. Elliott (MRC-University of Glasgow Centre for Virus Research) , Oliver G. Pybus (University of Oxford) , Dennis R. Burton (The Scripps Research Institute; Ragon Institute of MGH, Harvard; MIT) , Roger Hewson (Public Health England) , Katie J. Doores (Kings College London) , Thomas A. Bowden (Wellcome Centre for Human Genetics, University of Oxford; The Scripps Research Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 25 , PAGES 3750 - 3758.e4

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 14744

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.

Journal Keywords: phlebovirus; Rift Valley fever virus; antibody; structure; bunyavirus; virus-host interactions; immune response; vaccine; antiviral; neutralization

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Documents:
1-s2.0-S2211124718319120-main.pdf