Herpes simplex virus immune evasion from antibody and complement

Herpes simplex virus type 1 (HSV-1) evades immunity mediated by antibody and complement. HSV-1 glycoproteins E (gE) and I (gI) encode a viral IgG Fc receptor (vFcgammaR) that blocks functions mediated by IgG. HSV-1 glycoprotein C (gC1) binds complement component C3b and inhibits the interaction of C5 and properdin (P) with Cab, blocking activation of both the classical and alternative complement pathways. Herpes simplex virus type 2 (HSV-2) encodes homologues of gE, gI, and gC, yet despite the significance of HSV-2 in human disease, relatively few studies address the complement evasion strategies used by this virus. In this dissertation, I examined the significance of HSV-2 gC (gC2) in immune evasion. Three independently derived wild type (WT) and gC2null virus pairs were compared to evaluate the mechanisms by which gC2 protects cell-free virus from complement-mediated neutralization; to determine whether gC2 protects infected cells from complement-mediated cell lysis; and to examine whether gC2 contributes to viral pathogenesis in vivo. Additional studies were performed to evaluate whether blocking immune evasion has potential therapeutic value in human immunodeficiency virus (HIV) patients. gC2 prevents complement-mediated neutralization induced by natural IgM antibody and the classical complement pathway. Natural IgM antibody in nonimmune human serum bound to HSV-2 gCnull virus and neutralized through a mechanism that required C1q and involved both C3 and C5, but not the formation of the membrane attack complex. Interestingly, HSV antibody-negative sera obtained from four individuals differed in potency of complement-mediated virus neutralization, indicating that innate immunity offers variable protection against HSV. gC2 contributes to viral pathogenesis. All gC2null viruses examined were significantly attenuated in the murine flank model of infection compared with WT strains. In C3 knockout mice, disease severity increased to levels comparable with WT virus for two HSV-2 strains, indicating that the virulence conferred by gC2 was through interaction with complement. Finally, studies examining complement and HSV antibody neutralization in HIV infected subjects support a significant contribution for gC and gE in preventing antibody and complement mediated neutralization, and indicate that gC and gE immune evasion domains shield critical neutralizing epitopes on viral glycoproteins involved in entry.