Dengue virus neutralization is modulated by IgG antibody subclass and Fcγ receptor subtype

Severe dengue virus (DENV) infection is epidemiologically linked to pre-existing anti-DENY antibodies acquired by maternal transfer or primary infection. A possible explanation is that DENY immune complexes evade neutralization by engaging Fc gamma receptors (Fc gamma R) on monocytes, natural targets for DENV in humans. Using epitope-matched humanized monoclonal antibodies (mAbs) and stable Fc gamma R-transfected CV-1 cells, we found that DENY neutralization by IgG1, IgG3, and IgG4 mAbs was enhanced in high-affinity Fc gamma RIA transfectants and diminished in low-affinity Fc gamma RIIA transfectants, whereas neutralization by IgG2 mAbs (low-affinity ligands for both Fc gamma Rs) was diminished equally. In Fc gamma R-negative Vero cells, IgG3 mAbs exhibited the strongest neutralizing activity and IgG2, the weakest. Our results demonstrate that DENY neutralization is modulated by the Fc region in an IgG subclass manner, likely through effects on virion and Fc gamma R binding. Thus, the IgG antibody subclass profile generated by DENY infection or vaccination may independently influence the magnitude of the neutralizing response. (C) 2009 Elsevier Inc. All rights reserved.