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Characterization of a potent and highly unusual minimally enhancing antibody directed against dengue virus

DOI: 10.1038/s41590-018-0227-7 DOI Help

Authors: Max Renner (Wellcome Trust Centre for Human Genetics, University of Oxford) , Aleksandra Flanagan (Wellcome Trust Centre for Human Genetics, University of Oxford) , Wanwisa Dejnirattisai (Wellcome Trust Centre for Human Genetics, University of Oxford) , Chunya Puttikhunt (Mahidol University) , Watchara Kasinrerk (Chiang Mai University) , Piyada Supasa (Wellcome Trust Centre for Human Genetics, University of Oxford) , Wiyada Wongwiwat (Wellcome Trust Centre for Human Genetics, University of Oxford) , Kriangkrai Chawansuntati (Mahidol University) , Thaneeya Duangchinda (Mahidol University) , Alison Cowper (Wellcome Trust Centre for Human Genetics, University of Oxford) , Claire M. Midgley (Wellcome Trust Centre for Human Genetics, University of Oxford) , Prida Malasit (Wellcome Trust Centre for Human Genetics, University of Oxford) , Juha T. Huiskonen (Wellcome Trust Centre for Human Genetics, University of Oxford) , Juthathip Mongkolsapaya (Wellcome Trust Centre for Human Genetics, University of Oxford) , Gavin R. Screaton (Wellcome Trust Centre for Human Genetics, University of Oxford) , Jonathan M. Grimes (Wellcome Trust Centre for Human Genetics, University of Oxford; Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Immunology , VOL 496

State: Published (Approved)
Published: October 2018
Diamond Proposal Number(s): 8423

Abstract: Dengue virus is a major pathogen, and severe infections can lead to life-threatening dengue hemorrhagic fever. Dengue virus exists as four serotypes, and dengue hemorrhagic fever is often associated with secondary heterologous infections. Antibody-dependent enhancement (ADE) may drive higher viral loads in these secondary infections and is purported to result from antibodies that recognize dengue virus but fail to fully neutralize it. Here we characterize two antibodies, 2C8 and 3H5, that bind to the envelope protein. Antibody 3H5 is highly unusual as it not only is potently neutralizing but also promotes little if any ADE, whereas antibody 2C8 has strong capacity to promote ADE. We show that 3H5 shows resilient binding in endosomal pH conditions and neutralizes at low occupancy. Immunocomplexes of 3H5 and dengue virus do not efficiently interact with Fcγ receptors, which we propose is due to the binding mode of 3H5 and constitutes the primary mechanism of how ADE is avoided.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography