CMV-encoded Fcγ receptors: modulators at the interface of innate and adaptive immunity

The constant region of IgG antibodies mediates antiviral activities upon engaging host Fc gamma receptors (Fc gamma Rs) expressed by a variety of immune cells, such as antibody-dependent cellullar cytotoxcity (ADCC) executed by natural killer (NK)cells. Human cytomegalovirus (HCMV) is unique among viruses by encoding also an array of several Fc gamma-binding glycoproteins with cell surface disposition and concomitant incorporation into the virion. Evidence is increasing that the virus-encoded Fc gamma receptors differ in their Fc gamma binding mode but effectively operate as adversaries of host Fc gamma Rs since they are able to prevent IgG-mediated triggering of activating host Fc gamma Rs, i.e., Fc gamma RI, Fc gamma RIIA, and Fc gamma RIIIA. Here we discuss virus-encoded Fc gamma Rs as the first known HCMV inhibitors of IgG-mediated immunity which could account for the limited efficacy of HCMV hyperimmune globulin in clinical settings. A better understanding of their molecular mode of action opens up new perspectives for improving IgG therapies against HCMV disease.