Herpesviral Fcgamma 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.

Fig. 1

Structural composition of cellular and herpesviral FcγRs. Predicted immunoglobulin supergene family (IgSF)-like domains of cellular (left) and herpesviral (right) FcγRs are colour-coded based on their sequence relatedness. The Ig-like domains of the rodent CMV FcγRs are similarly distant to each of the three domains of cFcγRI. The α-herpesviral FcγR is composed by the gE:gI complex. gE but not gI exhibits a low sequence similarity to the second domain of cFcγRs . The Ig domains of FcγRII and FcγRIII are depicted in their bent orientation that is seen in the crystal structures. The domain arrangement in the other FcγRs is unknown.

Fig. 2

Herpesviral FcγRs protect against antiviral IgG by antibody-bipolar bridging. (A) Antiviral IgG binds to its cognate viral antigen on the surface of an infected cell or a virus particle via its Fab part. Upon binding, the Fc region recruits the C1q,r,s complex which activates the complement system via the classical pathway, resulting in antibody-dependent complement-mediated lysis (ADCL). (B) Alternatively, attachment of bound virus-specific IgG to cFcγR⁺-cytotoxic effector cells, e.g. NK cells, mediates cFcγR cross-linking and triggering of antibody-dependent cellular cytotoxicity (ADCC). (C) Antibody-bipolar bridging: viral FcγRs sequester the Fc part of bound antiviral IgG. This engagement blocks the recruitment of complement proteins or cFcγRs and thus mediates protection of the virus particle or infected cell from destruction.