title: Therapeutic efficacy of antibodies lacking Fcγ receptor binding against lethal dengue virus infection is due to neutralizing potency and blocking of enhancing antibodies [corrected].
abstract: 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.
authors: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, USA.
authors: Katherine L
authors: KL
authors: Williams
authors: Soila
authors: S
authors: Sukupolvi-Petty
authors: Martina
authors: M
authors: Beltramello
authors: Syd
authors: S
authors: Johnson
authors: Federica
authors: F
authors: Sallusto
authors: Antonio
authors: A
authors: Lanzavecchia
authors: Michael S
authors: MS
authors: Diamond
authors: Eva
authors: E
authors: Harris
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D003715:Dengue / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D006801:Humans; D020014:K562 Cells; D051379:Mice; D009500:Neutralization Tests; D011487:Protein Conformation; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D015996:Survival Rate; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; C489017:FCGR1A protein, human; D017452:Receptors, IgG; D014759:Viral Envelope Proteins