Therapeutic Efficacy of Antibodies Lacking FcγR against Lethal Dengue Virus Infection Is Due to Neutralizing Potency and Blocking of Enhancing Antibodies

PLoS Pathogens

Soila Sukupolvi-Petty¹  Michael S. Diamond¹  Katherine L. Williams²  Eva Harris²  Federica Sallusto³  Antonio Lanzavecchia³  Martina Beltramello³  Syd Johnson⁴ 

[1] Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America;Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, United States of America;Institute for Research in Biomedicine, Bellinzona, Switzerland;Macrogenics, Inc., Rockville, Maryland, United States of America

关键词: Antibodies;    Dengue virus;    Virions;    Cell fusion;    Immune serum;    West Nile virus;    Enzyme-linked immunoassays;    Stoichiometry;   

DOI  :  10.1371/journal.ppat.1003157

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease.

【 授权许可】

CC BY