title: The herpes simplex virus 1 IgG fc receptor blocks antibody-mediated complement activation and antibody-dependent cellular cytotoxicity in vivo.
abstract: Herpes simplex virus 1 (HSV-1) glycoprotein E (gE) mediates cell-to-cell spread and functions as an IgG Fc receptor (FcγR) that blocks the Fc domain of antibody targeting the virus or infected cell. Efforts to assess the functions of the HSV-1 FcγR in vivo have been hampered by difficulties in preparing an FcγR-negative strain that is relatively intact for spread. Here we report the FcγR and spread phenotypes of NS-gE264, which is a mutant strain that has four amino acids inserted after gE residue 264. The virus is defective in IgG Fc binding yet causes zosteriform disease in the mouse flank model that is only minimally reduced compared with wild-type and the rescue strains. The presence of zosteriform disease suggests that NS-gE264 spread functions are well maintained. The HSV-1 FcγR binds the Fc domain of human, but not murine IgG; therefore, to assess FcγR functions in vivo, mice were passively immunized with human IgG antibody to HSV. When antibody was inoculated intraperitoneally 20 h prior to infection or shortly after virus reached the dorsal root ganglia, disease severity was significantly reduced in mice infected with NS-gE264, but not in mice infected with wild-type or rescue virus. Studies of C3 knockout mice and natural killer cell-depleted mice demonstrated that the HSV-1 FcγR blocked both IgG Fc-mediated complement activation and antibody-dependent cellular cytotoxicity. Therefore, the HSV-1 FcγR promotes immune evasion from IgG Fc-mediated activities and likely contributes to virulence at times when antibody is present, such as during recurrent infections.
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6073, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Lubinski
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.forename: Sita
authors.initials: S
authors.lastname: Awasthi
authors.forename: Fushan
authors.initials: F
authors.lastname: Wang
authors.forename: Harvey M
authors.initials: HM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency / Q000276:immunology; D004195:Disease Models, Animal; D006562:Herpes Zoster / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology; D047589:Leukocyte Reduction Procedures; D051379:Mice; D008807:Mice, Inbred BALB C; D012720:Severity of Illness Index; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D003176:Complement C3; D014759:Viral Envelope Proteins; D037521:Virulence Factors; C044768:glycoprotein E, herpes simplex virus type 1