Abstract

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 cell-mediated 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. Graphical AbstractNK cells elicit a powerful antibody-mediated antiviral response through ADCC. gp68 (ochroid) binds IgG in a 2:1 ratio reducing, but not abolishing accessibility of immune complexes to Fc{gamma}RIII+ (dark blue) immune effector cells such as NK cells. gp34 (red, natively forming a dimer (Sprague et al., 2008)) effectively internalizes immune complexes making them unavailable to surveilling Fc{gamma}RIII+ effector cells but cannot compete with Fc{gamma}RIII for a similar binding region on IgG. Supported by functional evaluation, we propose a model in which g34 and gp68 work in cooperation to achieve efficient antagonization of antibody-mediated effector mechanisms. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY