Human Cytomegalovirus antagonizes activation of Fcγ receptors II and III by distinct and synergizing modes of IgG manipulation

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