Herpesviral Fcγ receptors: culprits attenuating antiviral IgG?

Abstract

Production of IgG in response to virus infection is central to antiviral immune effector functions and a hallmark of B cell memory. Antiviral antibodies (Abs) recognising viral glycoproteins or protein antigen displayed on the surface of virions or virus-infected cells are crucial in rendering the virus noninfectious and in eliminating viruses or infected cells, either acting alone or in conjunction with complement. In many instances, passive transfer of Abs is sufficient to protect from viral infection. Herpesviruses (HV) are equipped with a large array of immunomodulatory functions which increase the efficiency of infection by dampening the antiviral immunity. Members of the alpha- and beta-subfamily of the Herpesviridae are distinct in encoding transmembrane glycoproteins which selectively bind IgG via its Fc domain. The Fc-binding proteins constitute viral Fcgamma receptors (vFcgammaRs) which are expressed on the cell surface of infected cells. Moreover, vFcgammaRs are abundantly incorporated into the envelope of virions. Despite their molecular and structural heterogeneity, the vFcgammaRs generally interfere with IgG-mediated effector functions like antibody (Ab)-dependent cellular cytolysis, complement activation and neutralisation of infectivity of virions. vFcgammaRs may thus contribute to the limited therapeutic potency of antiherpesviral IgG in clinical settings. A detailed molecular understanding of vFcgammaRs opens up the possibility to design recombinant IgG molecules resisting vFcgammaRs. Engineering IgG with a better antiviral efficiency represents a new therapeutic option against herpesviral diseases.

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

“…According to our data, the effect of these immunoevasins was bypassed by Abmediated NK cell activation, yet we did not directly address their capacity to influence ADCC. Moreover, in our experimental system, immune sera were capable of triggering NK cell activation against infected cells despite the possible interference by gp34 and gp68 HCMV Fc-binding proteins (47,48). Coincident results are seen using cells infected with HSV-1, also encoding a decoy FcgR (M. Moraru, L.E.…”

Antibody-mediated protection against genital herpes simplex virus type 2 disease in mice by Fc gamma receptor-dependent and -independent mechanisms

“…HSV has evolved mechanisms to inhibit Ab function in humans, thereby enhancing virus pathogenicity. HSV encoded glycoprotein E and glycoprotein I complexes are incorporated in both virion and infected cell membranes and may serve as an Fc receptor capable of binding human IgG Ab and inhibiting Ab effector functions (Budt et al, 2004). However, the extent to which this putative immune evasion mechanism impacts pathogenesis in humans is not well understood.…”

A novel assay for detecting virus-specific antibodies triggering activation of Fcγ receptors

“…HA and F or G, F and SH, respectively, which reach a high density on the cell surface (Forthal et al, 1993(Forthal et al, , 1994Osiowy et al, 1994;Cane et al, 1996;Wu et al, 2005). With regard to HCMV, several features of the virus are likely to dampen the FcγR activating efficiency of the IgG response: i) the expression of virusencoded FcγRs binding to the Fc domain of HCMV-immune IgG thus preventing host FcγR activation (Sprague et al, 2008;Lilley et al, 2001;Budt et al, 2004;Atalay et al, 2002) and (Corrales-Aguilar, E.; Merce-Maldonado, E. and Hengel, H. unpublished observation); ii) retrieval of highly immunogenic neutralizing glycoproteins like gB from the cell surface resulting in very low surface densities (Radsak et al, 1996) and iii) a considerable sequence variability of certain nonessential transmembrane glycoprotein-encoding genes encoding potential IgG targets on infected cells (Dolan et al, 2004). These features further imply that the antigen display between HCMV particles and infected target cells substantially differs.…”