TY - JOUR
T1 - The human immune response to dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity
AU - Beltramello, Martina
AU - Williams, Katherine L.
AU - Simmons, Cameron P.
AU - MacAgno, Annalisa
AU - Simonelli, Luca
AU - Quyen, Nguyen Than Ha
AU - Sukupolvi-Petty, Soila
AU - Navarro-Sanchez, Erika
AU - Young, Paul R.
AU - De Silva, Aravinda M.
AU - Rey, Félix A.
AU - Varani, Luca
AU - Whitehead, Stephen S.
AU - Diamond, Michael S.
AU - Harris, Eva
AU - Lanzavecchia, Antonio
AU - Sallusto, Federica
N1 - Funding Information:
We thank Michel Nussenzweig for providing vectors to clone and express Ig genes, David Jarrossay for cell sorting, Catriona McElnea for the NS1 screening, and Ruben Lachica for his excellent technical assistance with the in vivo experiments. This research was supported in part by the Gottfried and Julia Bangerter-Rhyner-Stiftung (to F.S.), the Swiss National Science Foundation Grant N. 126027 (to A.L.), the Swiss Vaccine Research Institute (to L.V.), the Wellcome Trust (to C.P.S.), the Pediatric Dengue Vaccine Initiative (CRA14 to E.H.), NIH grant R01-AI077955 (to M.S.D.), AI65359 (to E.H.), and U19-AI 057266 (to A.L.) and by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, NIH (to S.S.W.). The Institute for Research in Biomedicine is supported by the Helmut Horten Foundation. A.L. is the scientific founder of Humabs LLC and a member of its Board of Directors. A.L. and F.S. are shareholders of Humabs.
PY - 2010/9/16
Y1 - 2010/9/16
N2 - Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fcγ receptors (FcγR). 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 FcγR 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.
AB - Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fcγ receptors (FcγR). 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 FcγR 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.
UR - https://www.scopus.com/pages/publications/77956605864
U2 - 10.1016/j.chom.2010.08.007
DO - 10.1016/j.chom.2010.08.007
M3 - Article
C2 - 20833378
AN - SCOPUS:77956605864
SN - 1931-3128
VL - 8
SP - 271
EP - 283
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -