Blocking antibody access to neutralizing domains on glycoproteins involved in entry as a novel mechanism of immune evasion by herpes simplex virus type 1 glycoproteins C and E.
Herpes simplex virus type 1 (HSV-1) glycoprotein C (gC) blocks complement activation, and glycoprotein E (gE) interferes with IgG Fc-mediated activities. While evaluating gC- and gE-mediated immune evasion in human immunodeficiency virus (HIV)-HSV-1-coinfected subjects, we noted that antibody alone was more effective at neutralizing a strain with mutations in gC and gE (gC/gE) than a wild-type (WT) virus. This result was unexpected since gC and gE are postulated to interfere with complement-mediated neutralization. We used pooled human immunoglobulin G (IgG) from HIV-negative donors to confirm the results and evaluated mechanisms of the enhanced antibody neutralization. We demonstrated that differences in antibody neutralization cannot be attributed to the concentrations of HSV-1 glycoproteins on the two viruses or to the absence of an IgG Fc receptor on the gC/gE mutant virus or to enhanced neutralization of the mutant virus by antibodies that target only gB, gD, or gH/gL, which are the glycoproteins involved in virus entry. Since sera from HIV-infected subjects and pooled human IgG contain antibodies against multiple glycoproteins, we determined whether differences in neutralization become apparent when antibodies to gB, gD, or gH/gL are used in combination. Neutralization of the gC/gE mutant was greatly increased compared that of WT virus when any two of the antibodies against gB, gD, or gH/gL were used in combination. These results suggest that gC and gE on WT virus provide a shield against neutralizing antibodies that interfere with gB-gD, gB-gH/gL, or gD-gH/gL interactions and that one function of virus neutralization is to prevent interactions between these glycoproteins.
Hook
Lauren M
LM
Infectious Disease Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Huang
Jialing
J
Jiang
Ming
M
Hodinka
Richard
R
Friedman
Harvey M
HM
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D000939:Epitopes / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D009500:Neutralization Tests; D011485:Protein Binding; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism
D000914:Antibodies, Viral; D000939:Epitopes; D007074:Immunoglobulin G; D014759:Viral Envelope Proteins; C044768:glycoprotein E, herpes simplex virus type 1; C038535:glycoprotein gC, herpes simplex virus type 1