HERPES-SIMPLEX VIRUS GLYCOPROTEIN-C - MOLECULAR MIMICRY OF COMPLEMENTREGULATORY PROTEINS BY A VIRAL PROTEIN

Herpes simplex virus (HSV) encodes a protein, glycoprotein C (gC), whi ch binds to the third complement component, the central mediator of co mplement activation. In this study the structural and functional relat ionships of gC from HSV type 1 (HSV-1) and known human complement regu latory proteins factor H, properdin, factor B, complement receptor 1 ( CR1) and 2 (CR2) were investigated. The interaction of gC with C3b was studied using purified complement components, synthetic peptides, ant isera against different C3 fragments and anti-C3 monoclonal antibodies (mAb) with known inhibitory effects on C3-ligand interactions. All th e mAb that inhibited gC/C3b interactions, in a differential manner, al so prevented binding of C3 fragments to factors H, B, CR1 or CR2. No b locking was observed with synthetic peptides representing different C3 regions or with factor B and C3d, whereas C3b, C3c and factor H were inhibitory, as well as purified gC. There was no binding of gC to cobr a venom factor (CVF), a C3c-like fragment derived from cobra gland. Pu rified gC bound to iC3, iC3b and C3c, but failed to bind to C3d. Glyco protein C bound only weakly to iC3 derived from bovine and porcine pla sma, thus indicating a preference of the viral protein for the appropr iate host. Binding of gC was also observed to proteolytic C3 fragments , especially to the beta-chain, thus suggesting the importance of the C3 region as a binding site. Purified gC from HSV-1, but not HSV-2, in hibited the binding of factor H and properdin but not of CR1 to C3b. T he binding of iC3b to CR2, a molecule involved in B-cell activation an d binding of the Epstein-Barr virus, was also inhibited by the HSV-1 p rotein. As factor H and properdin, the binding of which was inhibited by gC, are important regulators of the alternative complement pathway, these data further support a role of gC in the evasion of HSV from a major first-line host defence mechanism, i.e. the complement system. I n addition, the inhibition of the C3/CR2 interaction may suggest a pos sible immunoregulatory role of HSV glycoprotein C.