Mucosal IgG Interacts with Herpes Simplex Virus Glycoprotein E, an Fcγ Receptor Mimetic, and Neutralizes Viral Infection: Activity is Reduced in the Setting of Vaginal Dysbiosis.

Abstract

Small studies have documented variable neutralizing activity of cervicovaginal lavage (CVL) against herpes simplex viruses (HSV). This neutralizing activity is lower in women with bacterial vaginosis (BV), a syndrome associated with HSV recurrences. However, the mechanisms have not been fully defined. We took advantage of a biobank of CVL and linked data including HSV neutralizing activity measured by plaque reduction assay, Nugent scores and concentrations of CVL immune mediators. We fractionated CVL to enrich or deplete candidates and quantified neutralizing activity. CVL reduced viral plaque formation by 40.82 ± 37.59% (mean ± SD, n=361). Activity was independent of HSV serostatus, significantly lower in those with a Nugent score of 7-10 (n=176, p<0.05) and correlated positively with CVL concentrations of IgG (p=0.001, n=87) and HNP1-3 (p<0.001, n=119). Activity was enriched in the immunoglobulin fraction but was reduced when IgG (but not IgA) was depleted. Increasing concentrations of an anti-glycoprotein E (gE) monoclonal antibody overcame the neutralizing activity, suggesting that interactions between IgG Fc and gE, a viral Fc gamma receptor, contribute. Moreover, CVL had less HSV inhibitory activity against a gE-null virus. Treatment of CVL with Peptide-N-Glycosidase F, which cleaves IgG N-glycans, reduced HSV neutralizing activity. Interactions between IgG Fc and viral gE, independent of Fab specificity, contribute to cervicovaginal antiviral activity. Antiviral activity is reduced with dysbiosis, presumably reflecting lower IgG levels and differences in N-glycans that lead to decreased gE interactions. Results highlight the importance of developing and implementing strategies to protect against vaginal dysbiosis.