Novel mechanism of antibody-independent complement neutralization of herpes simplex virus type 1

The envelope surface glycoprotein C (gC) of HSV-1 interferes with the compl ement cascade by binding C3 and activation products C3b, iC3b, and C3c, and by blocking the interaction of C5 and properdin with C3b, Wild-type HSV-1 is resistant to Ab-independent complement neutralization; however, HSV-1 mu tant virus lacking gC is highly susceptible to complement resulting in grea ter than or equal to 100-fold reduction in virus titer, We evaluated the me chanisms by which complement inhibits HSV-I gC null virus to better underst and how gC protects against complement-mediated neutralization. Cg-depleted serum prepared from an HSV-1 and -2 Ab-negative donor neutralized gC null virus comparable to complement-intact serum, indicating that Cg and termina l lytic activity are not required, In contrast, C5-depleted serum from the same donor failed to neutralize gC null virus, supporting a requirement for C5, EDTA-treated serum did not neutralize gC null virus, indicating that c omplement activation is required. Factor D-depleted and C6-depleted sera ne utralized virus, suggesting that the alternative complement pathway and com plement components beyond C5 are not required, Complement did not aggregate virus or block attachment to cells, However, complement inhibited infectio n before early viral gene expression, indicating that complement affects on e or more of the following steps in virus replication: virus entry, uncoati ng, DNA transport to the nucleus, or immediate early gene expression, There fore, in the absence of gC, HSV-1 is readily inhibited by complement by a C S-dependent mechanism that does not require viral lysis, aggregation, or bl ocking virus attachment.