A Model System to Investigate Antibody Bipolar Bridging Mediated by gE-gI, a Herpes Virus Fc Receptor

The Herpes Simplex Virus 1 (HSV-1) expresses two membrane glycoproteins (gE and gI) that bind the Fc region of host immunoglobulin G (IgG), which allows HSV-infected cells to escape recognition by Fc-dependent immune cells. HSV-1 gE-gI can further undermine the immune system by participating in antibody bipolar bridging (ABB), a process by which the antigen-binding fragments of the IgG bind a viral antigen while the Fc binds to gE-gI. The fate of the gE-gI/IgG/viral antigen ABB complex is still unknown. In this study, we engineered an in vitro ABB system to determine whether the gE-gI/IgG/viral antigen complex is internalized and targeted for degradation in host cells. This system involves HeLa cells transiently expressing HSV-1 gE-gI and HSV-1 gD; and two forms of the monoclonal anti-gD antibody: one in which the Fabs were fused to a human IgG1 Fc (hIgG), which can bind to gE-gI via its Fc and to gD via its Fabs, and one in which the Fabs were fused to a mouse IgG2a Fc (mIgG), which can bind to gD but not to gE-gI. A hIgG against an irrelevant HIV-1 antigen was used as a control. Time-lapse confocal imaging showed that gE-gI internalized hIgG/gD but not mIgG/gD; internalized IgG and gD were targeted into degradative compartments. These results suggest that gE-gI plays an active role in clearing the infected cell surface of both host IgG and viral antigens, providing HSV-1 with a mechanism to evade the immune responses