Journal
CELL HOST & MICROBE
Volume 8, Issue 3, Pages 271-283Publisher
CELL PRESS
DOI: 10.1016/j.chom.2010.08.007
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Funding
- Gottfried and Julia Bangerter-Rhyner-Stiftung
- Swiss National Science Foundation [126027]
- Swiss Vaccine Research Institute
- Wellcome Trust
- Pediatric Dengue Vaccine Initiative [CRA14]
- NIH [R01-AI077955, AI65359, U19-AI 057266]
- Helmut Horten Foundation
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Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fc gamma receptors (Fc gamma R). We immortalized memory B cells from individuals after primary or secondary infection and analyzed anti-DENV monoclonal antibodies (mAbs) thus generated. MAbs to envelope (E) protein domain III (DIII) were either serotype specific or cross-reactive and potently neutralized DENV infection. DI/DII- or viral membrane protein prM-reactive mAbs neutralized poorly and showed broad cross-reactivity with the four DENV serotypes. All mAbs enhanced infection at subneutralizing concentrations. Three mAbs targeting distinct epitopes on the four DENV serotypes and engineered to prevent Fc gamma R binding did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection. Our findings reveal an unexpected degree of cross-reactivity in human antibodies against DENV and illustrate the potential for an antibody-based therapy to control severe dengue.
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