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Impact of Microbicide Formulation on Glycosylation and Innate Immunity in Cervicovaginal Fluid

Glycosylation is a key component in the establishment of healthy symbiotic bacterial colonization patterns and is involved in the maintenance of mucosal barriers to infection, regulating both adaptive and innate immunity. Changes in glycosylation state have powerful effects on the stabilization and activation of antibodies and can alter the microbicidal effects of immune molecules. Thus glycome is both a marker and modulator of innate immunity. We recently showed a strong correlation between glycosylation status in the cervicovaginal (CVL) fluid and microbiome status, using lectin microarray analysis. Here, we report on the impact of thin film versus hydrogel placebos, for vaginal delivery of drugs, on the glycosylation status and innate antiviral immunity of CVL fluids. CVL samples from 52 women were studied for glycosylation status using lectin microarray analysis and their impact on the infectivity of herpes simplex virus 1 & 2 (collectively HSV) and HIV‐1 using Plaque and TZM‐bl assays respectively. In our studies, we identified lower levels of high‐mannose, as indicated by the high‐mannose binding lectins griffithsin (GRFT) and scytovirin (SVN) that correlated with lower anti‐HIV‐1 (SVN, p = 0.02; n= 90; t‐test) and anti‐HSV activities (GRFT, p=0.001; n= 139; t‐test). We also found that the drug delivery mode has a significant impact on the glycan composition of the CVL, which in turn may affect innate immunity. Gel use had a greater impact on the glycome with a significant loss of high‐mannose signature (GRFT, p = 0.008; SVN, p = 0.01; n= 53; paired t‐test). GRFT immobilized on agarose beads were used to isolate GRFT‐binding glycoproteins in the CVL and a proteomic analysis on those samples identified a number of protease inhibitors that were previously associated with reduced susceptibility to HIV infection. Collectively, our data suggests that high‐mannose in the CVL is a marker for anti‐viral activity and that thin films do not impact the innate anti‐viral immunity in the CVL.