title: Dengue virus neutralization is modulated by IgG antibody subclass and Fcgamma receptor subtype.
abstract: Severe dengue virus (DENV) infection is epidemiologically linked to pre-existing anti-DENV antibodies acquired by maternal transfer or primary infection. A possible explanation is that DENV immune complexes evade neutralization by engaging Fcgamma receptors (FcgammaR) on monocytes, natural targets for DENV in humans. Using epitope-matched humanized monoclonal antibodies (mAbs) and stable FcgammaR-transfected CV-1 cells, we found that DENV neutralization by IgG1, IgG3, and IgG4 mAbs was enhanced in high-affinity FcgammaRIA transfectants and diminished in low-affinity FcgammaRIIA transfectants, whereas neutralization by IgG2 mAbs (low-affinity ligands for both FcgammaRs) was diminished equally. In FcgammaR-negative Vero cells, IgG3 mAbs exhibited the strongest neutralizing activity and IgG2, the weakest. Our results demonstrate that DENV neutralization is modulated by the Fc region in an IgG subclass manner, likely through effects on virion and FcgammaR binding. Thus, the IgG antibody subclass profile generated by DENV infection or vaccination may independently influence the magnitude of the neutralizing response.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA.
authors.forename: W W Shanaka I
authors.initials: WW
authors.lastname: Rodrigo
authors.forename: Olivia K T
authors.initials: OK
authors.lastname: Block
authors.forename: Christopher
authors.initials: C
authors.lastname: Lane
authors.forename: Soila
authors.initials: S
authors.lastname: Sukupolvi-Petty
authors.forename: Ana P
authors.initials: AP
authors.lastname: Goncalvez
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Ching-Juh
authors.initials: CJ
authors.lastname: Lai
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rose
authors.forename: Xia
authors.initials: X
authors.lastname: Jin
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Schlesinger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000145:classification / Q000378:metabolism*; D000914:Antibodies, Viral / Q000145:classification / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003715:Dengue / Q000276:immunology / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000145:classification / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D009500:Neutralization Tests; D002679:Pan troglodytes; D017452:Receptors, IgG / Q000145:classification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014709:Vero Cells
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins