title: Generation of Monoclonal Antibodies against Dengue Virus Type 4 and Identification of Enhancing Epitopes on Envelope Protein.
abstract: The four serotypes of dengue virus (DENV1-4) pose a serious threat to global health. Cross-reactive and non-neutralizing antibodies enhance viral infection, thereby exacerbating the disease via antibody-dependent enhancement (ADE). Studying the epitopes targeted by these enhancing antibodies would improve the immune responses against DENV infection. In order to investigate the roles of antibodies in the pathogenesis of dengue, we generated a panel of 16 new monoclonal antibodies (mAbs) against DENV4. Using plaque reduction neutralization test (PRNT), we examined the neutralizing activity of these mAbs. Furthermore, we used the in vitro and in vivo ADE assay to evaluate the enhancement of DENV infection by mAbs. The results indicate that the cross-reactive and poorly neutralizing mAbs, DD11-4 and DD18-5, strongly enhance DENV1-4 infection of K562 cells and increase mortality in AG129 mice. The epitope residues of these enhancing mAbs were identified using virus-like particle (VLP) mutants. W212 and E26 are the epitope residues of DD11-4 and DD18-5, respectively. In conclusion, we generated and characterized 16 new mAbs against DENV4. DD11-4 and D18-5 possessed non-neutralizing activities and enhanced viral infection. Moreover, we identified the epitope residues of enhancing mAbs on envelope protein. These results may provide useful information for development of safe dengue vaccine.
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Chung-Tao
authors: CT
authors: Tang
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Mei-Ying
authors: MY
authors: Liao
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Chien-Yu
authors: CY
authors: Chiu
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Wen-Fan
authors: WF
authors: Shen
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Chiung-Yi
authors: CY
authors: Chiu
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Ping-Chang
authors: PC
authors: Cheng
authors: Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, United States Department of Health and Human Services, Fort Collins, Colorado, United States of America.
authors: Gwong-Jen J
authors: GJ
authors: Chang
authors: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors: Han-Chung
authors: HC
authors: Wu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D015153:Blotting, Western; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins