In Vivo Immune Evasion Mediated by the Herpes Simplex Virus Type 1 Immunoglobulin G Fc Receptor

Abstract

Herpes simplex virus (HSV) glycoproteins gE and gI form an immunoglobulin G (IgG) Fc receptor (FcγR) that binds the Fc domain of human anti-HSV IgG and inhibits Fc-mediated immune functions in vitro. gE or gI deletion mutant viruses are avirulent, probably because gE and gI are also involved in cell-to-cell spread. In an effort to modify FcγR activity without affecting other gE functions, we constructed a mutant virus, NS-gE339, that has four amino acids inserted into gE within the domain homologous to mammalian IgG FcγRs. NS-gE339 expresses gE and gI, is FcγR−, and does not participate in antibody bipolar bridging since it does not block activities mediated by the Fc domain of anti-HSV IgG. In vivo studies were performed with mice because the HSV-1 FcγR does not bind murine IgG; therefore, the absence of an FcγR should not affect virulence in mice. NS-gE339 causes disease at the skin inoculation site comparably to wild-type and rescued viruses, indicating that the FcγR− mutant virus is pathogenic in animals. Mice were passively immunized with human anti-HSV IgG and then infected with mutant or wild-type virus. We postulated that the HSV-1 FcγR should protect wild-type virus from antibody attack. Human anti-HSV IgG greatly reduced viral titers and disease severity in NS-gE339-infected animals while having little effect on wild-type or rescued virus. We conclude that the HSV-1 FcγR enables the virus to evade antibody attack in vivo, which likely explains why antibodies are relatively ineffective against HSV infection.

In Vivo Role of Complement-Interacting Domains of Herpes Simplex Virus Type 1 Glycoprotein Gc

“…We have previously described a humoral immune evasion domain on glycoprotein gE that inhibits IgG Fc-mediated functions (4)(5)(6). We showed that gE blocks complementenhanced antibody neutralization, reducing the effectiveness of antibody 100-fold in vitro and offering highly significant protection to the virus or virus-infected cell against antibodies in vivo (6). The results of this study indicate that complement has little effect on wild-type virus, as disease scores of wild-type virus are virtually identical in C3 knockout and complement-intact mice.…”

Herpesviral Fcγ receptors: culprits attenuating antiviral IgG?

“…In mice passively immunised with human anti-HSV-IgG, titers of a gE mutant with a 4-aa insert disrupting the region homologous to mammalian FcgRs were significantly reduced, whereas wild-type HSV remained unaffected. [94]. The minimal mutation introduced into the gE mutants affected the IgG-related functions of gE:gI, but did not interfere with the other important gE function, i.e.…”

Complement and its role in protection and pathogenesis of flavivirus infections

“…To minimize recognition and/or destruction by complement several different families of viruses have evolved strategies to evade or exploit complement to establish infection (reviewed in [83][84][85][86][87]). Complement evasion mechanisms include: (a) use of complement receptors to enhance viral entry or suppress adaptive immune response (e.g., HIV, West Nile virus (WNV), measles virus, adenoviruses, herpesviruses, enteroviruses, hepatitis B and C viruses ); (b) expression of viral proteins that directly inhibit complement (e.g., herpesviruses, coronaviruses, and astroviruses [127][128][129][130][131][132][133][134][135][136]); (c) modulation of expression of complement regulators on host cells to prevent complement-dependent lysis (e.g., herpesviruses [137][138][139]); (d) incorporation of human regulators on the surface of virions to protect from complement-mediated virolysis (e.g. HIV, HTLV, cytomegalovirus, and vaccinia virus [140][141][142][143][144][145][146]); (e) recruitment of soluble complement regulatory proteins to the virion or infected cell surface (e.g., WNV and HIV [147][148][149][150][151]); (f) expression of viral decoy proteins that structurally or functionally mimic complement regulatory proteins (e.g., poxviruses and herpesviruses [152][153][154][155][156][157][158][159].…”