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 (FcγR) mediated immune control mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). We have previously shown that HCMV avoids FcγR activation by concomitant expression of the viral Fc-gamma-binding glycoproteins (vFcγRs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fcγ sites and achieve efficient antagonization of host FcγR activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host FcγR binding to immune complexes. In doing so, gp68 induces Fcγ accessibility to gp34 and simultaneously limits host FcγR 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.
Highlights
Human cytomegalovirus (HCMV) constitutes the prototypical human pathogenic b-herpesvirus found worldwide with high immunoglobulin G (IgG) sero-prevalence rates of 56–94% depending on the respective countries (Zuhair et al, 2019)
We showed that HCMV gp34, gp68 and HSV-1 gE/gI efficiently antagonize the activation of human Fc-gamma receptor (FcgR)
In HCMV gB, a non-Fcg-binding HCMV encoded envelope glycoprotein, the location of two such motifs is further away from the transmembrane domain indicating it being destined for general endocytosis rather than immediate degradation, which is shared by another HCMV viral Fc-gamma-binding glycoproteins (vFcgRs), gpRL13, found primarily in intracellular compartments as well as HSV-1 gE, forming a heterodimeric gE/gI vFcgR described to internalize IgG and recycle back to the cell surface (Figure 3—figure supplement 1; Bonifacino and Traub, 2003; Cortese et al, 2012; Ndjamen et al, 2016; Sprague et al, 2004)
Summary
Human cytomegalovirus (HCMV) constitutes the prototypical human pathogenic b-herpesvirus found worldwide with high immunoglobulin G (IgG) sero-prevalence rates of 56–94% depending on the respective countries (Zuhair et al, 2019). We recently found Rhesus CMV (RhCMV) to encode an Fcg-binding protein in the Rh05 gene (RL11 gene family) seemingly more closely related to its HCMV analog (Kolb et al, 2019) This is supported by the fact that gpRh05, as HCMV vFcgRs gp and gp, is able to generically antagonize activation of all macaque FcgRs. While it is clear that by targeting the invariant part of the key molecule of the humoral immune response, vFcgRs have the potential to manipulate a multitude of antibody mediated immune functions, their role in vivo has yet to be determined. We show gp and gp to antagonize host FcgR activation by distinct but highly cooperative modes of Fcg targeting, leading to efficient evasion from antibody mediated immune control by division of labor
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