Immune evasion properties of herpes simplex virus type 1 glycoprotein gc

Abstract

Herpes simplex virus type 1 (HSV-1) glycoprotein gC binds complement (C') component C3b, and soluble gC inhibits C' activation. Two gC mutant viruses, unable to bind C3b, were compared with wild type and marker rescued viruses to evaluate the role of gC on the virion in protecting HSV-1 from C' neutralization. The gC mutant viruses were markedly susceptible to C' neutralization by nonimmune human serum, showing up to 5,000 fold decline in titer after 1 hour incubation with serum. In contrast, wild type or marker rescued viruses showed a 2 fold reduction in liter. Studies with agammaglobulinemic and IgG depleted serum indicated that C' neutralization did not require antibody. The kinetics of C' neutralization was rapid; the half-life of gC mutant strains in serum was 2-2'/2 minutes, compared with 1 hour for wild type virus. C' neutralized >50% of gC mutant virus up to serum dilutions of 1:40. Studies using EGTA-treated and C4 deficient serum support a role for the classical C' pathway in C' neutralization. The mechanism of C' neutralization was evaluated by measuring the effects of serum on blocking virus attachment to cells, and on aggregating or lysing virus. C' did not affect these steps. When virus attachment was allowed to proceed and C' added subsequently, virus infection was inhibited, suggesting a role for C' in neutralizing infection at a step after virus attachment. These results indicate that gC provides enormous protection to HSV-1 against neutralization by nonimmune serum, an immune evasion strategy for virus early in infection, before antibodies develop.