The Human Immune Response to Dengue Virus Is Dominated by Highly Cross-Reactive Antibodies Endowed with Neutralizing and Enhancing Activity

被引:470
作者
Beltramello, Martina [1 ]
Williams, Katherine L. [2 ]
Simmons, Cameron P. [3 ]
Macagno, Annalisa [1 ]
Simonelli, Luca [1 ]
Quyen, Nguyen Than Ha [3 ]
Sukupolvi-Petty, Soila [4 ,5 ,6 ]
Navarro-Sanchez, Erika [7 ]
Young, Paul R. [8 ]
de Silva, Aravinda M. [9 ]
Rey, Felix A. [7 ]
Varani, Luca [1 ]
Whitehead, Stephen S. [10 ]
Diamond, Michael S. [4 ,5 ,6 ]
Harris, Eva [2 ]
Lanzavecchia, Antonio [1 ]
Sallusto, Federica [1 ]
机构
[1] Inst Res Biomed, CH-6500 Bellinzona, Switzerland
[2] Univ Calif Berkeley, Div Infect Dis, Berkeley, CA 94720 USA
[3] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam
[4] Washington Univ, Dept Med, Sch Med, St Louis, MO 63110 USA
[5] Washington Univ, Dept Mol Microbiol, Sch Med, St Louis, MO 63110 USA
[6] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA
[7] Inst Pasteur, Dept Virol, F-75724 Paris, France
[8] Univ Queensland, Sch Chem & Mol Biosci, Ctr Infect Dis Res, Brisbane, Qld 4072, Australia
[9] Univ N Carolina, Dept Microbiol & Immunol, Sch Med, Chapel Hill, NC 27599 USA
[10] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA
基金
英国惠康基金; 瑞士国家科学基金会;
关键词
WEST-NILE-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; IMMUNOGLOBULIN G1 ANTIBODY; CHIMPANZEE FAB FRAGMENTS; BORNE ENCEPHALITIS-VIRUS; PROTEIN DOMAIN-III; ENVELOPE GLYCOPROTEIN; DEPENDENT ENHANCEMENT; HEMORRHAGIC-FEVER; MEDIATED NEUTRALIZATION;
D O I
10.1016/j.chom.2010.08.007
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:271 / 283
页数:13
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