HSV-2 gE2/gI2 are immune evasion molecules that bind IgG Fc to inhibit antibody-dependent cellular cytotoxicity

Introduction HSV-2 glycoproteins C, D, and E (gC2/gD2.gE2) are immunogens included in an experimental HSV-2 vaccine. We evaluated whether these antigens serve as targets for antibody-dependent cellular cytotoxicity (ADCC). Methods We transiently transfected HEK cells with gC2/gD2/gE2 DNA, added HSV-2 seropositive human convalescent sera (HCS), and measured surface CD107a expression on human NK cells by flow cytometry. Results We demonstrated that antibodies to gC2/gD2/gE2 mediate ADCC. HSV-2 gE and gI form a complex that binds IgG Fc. We next determined whether gE2/gI2 inhibits ADCC, a crucial function mediated by the IgG Fc, by comparing ADCC titers when HCS were added to cells transfected with gD2, gI2, and a gE2 mutant (gE2 MUT ) unable to bind IgG Fc or gD2, gI2, and gE2 wild-type (gE2 WT ). ADCC titers increased by 6.5-fold when cells were transfected with the gE2 MUT versus gE2 WT (P=0.01). We then spiked HCS with a gE2 mAb that blocks IgG Fc binding, or with a gE2 mAb that does not block IgG Fc binding. The blocking mAb significantly increased titers (P<0.0001), whereas a non-blocking gE2 mAb had no effect. Discussion We conclude that antibodies to gC2/gD2/gE are targets of ADCC, that gE2/gI2 inhibits ADCC, and that an mAb that targets the gE2 IgG Fc binding domain can prevent this inhibition.