University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; Wellcome Centre for Human Genetics; Mahidol University; National Science & Technology Development Agency - Thailand; National Center Genetic Engineering & Biotechnology (BIOTEC); Mahidol University; Chiang Mai University; National Science & Technology Development Agency - Thailand; National Center Genetic Engineering & Biotechnology (BIOTEC); Chiang Mai University; Diamond Light Source
Type
Article
Source Title
NATURE IMMUNOLOGY
Year
2018
Volume
19
Issue
11
Page
1248-+
Open Access
Green Accepted, Green Submitted
Publisher
NATURE PORTFOLIO
DOI
10.1038/s41590-018-0227-7
Format
PDF
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 Fc gamma receptors, which we propose is due to the binding mode of 3H5 and constitutes the primary mechanism of how ADE is avoided.
Funding Sponsor
Wellcome Trust, UK; Newton-Medical Research Council, UK [MR/NO12658/2]; National Institute for Health Research Oxford Biomedical Research Centre funding scheme; Thailand National Center for Genetic Engineering; and Biotechnology; Academy of Finland; Office of the Higher Education Commission; Mahidol University under the National Research Universities Initiative; Research Chair Grant from the National Science and Technology Development Agency (NSTDA), Thailand; Faculty of Medicine Siriraj Hospital, Mahidol University [(IO)R015936005]; Wellcome Trust [060208/Z/00/Z, 093305/Z/10/Z, 075491/Z/04, 095541/Z/11/Z, 203224/Z/16/Z, 204703/Z/16/Z, 080721/Z/06/Z]
License
Copyright
Rights
The Author(s), under exclusive licence to Springer Nature America, Inc.
