| Summary: | Herpes simplex virus type 1 (HSV-1) expresses a complex of two virally encoded glycoproteins, gE and gI, which has high affinity for nonimmune human IgG. The gE-gI complex has thus become known as an Fc receptor. This complex binds human IgG subclasses in the order IgG4 > IgG1 ≥ IgG2 but does not generally bind IgG3. This pattern of binding contrasts with that of mammalian Fc receptors including the human high affinity Fc receptor FcγRI and low affinity Fc receptors FcγRII and FcγRIII. Using recombinant IgG variants and cells infected with HSV-1, the binding specificity of the HSV-1 Fc receptor was investigated. The reported pattern of IgG subclass binding by the HSV-1 Fc receptor was confirmed. The use of IgG subclasses carrying mutations in the CH2 domain revealed that residues that have been implicated in mammalian FcγR binding have little importance for HSV-1 Fc receptor binding. Furthermore, unlike mammalian FcγR but in similarity to mammalian FcRn, HSV-1 Fc receptor binding was found to be independent of IgG glycosylation. Importantly, naturally occurring allotypes of IgG1 differing at one residue in the CH1 domain and at two residues in the CH3 domain showed striking differences in binding the HSV-1 Fc receptor but not mammalian FcγR. Using allotypic variants of IgG1 differing by as few as one amino acid it was demonstrated that the allotypic residues in both the CH1 and the CH3 domains affect binding of IgG1 to the HSV-1 Fc receptor. These results suggest functional differences between IgG1 allotypes that may explain their distribution in populations.
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