Human cytomegalovirus antagonizes activation of Fc gamma receptors by distinct and synergizing modes of IgG manipulation

Human cytomegalovirus (HCMV) is endowed with multiple highly sophisticated immune evasion strategies. This includes the evasion from antibody mediated immune control by counteracting host Fc-gamma receptor (Fc gamma R) mediated immune control mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). We have previously shown that HCMV avoids Fc gamma R activation by concomitant expression of the viral Fc-gamma-binding glycoproteins (vFc gamma Rs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fc gamma sites and achieve efficient antagonization of host Fc gamma R activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host Fc gamma R binding to immune complexes. In doing so, gp68 induces Fc gamma accessibility to gp34 and simultaneously limits host Fc gamma R recognition. The synergy of gp34 and gp68 is compelled by the interfering influence of excessive non-immune IgG ligands and highlights conformational changes within the IgG globular chains critical for antibody effector function.