Abstract
Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching. In women, genital inflammation (GI) significantly modifies HIV risk. However, the impact of GI on mucosal antibodies remains undefined. We investigated the impact of GI, pre-HIV infection, on antibody isotypes and IgG subclasses in the female genital tract. Immunoglobulin (Ig) isotypes, IgG subclasses and 48 cytokines were measured prior to HIV infection in cervicovaginal lavages (CVL) from 66 HIV seroconverters (cases) and 66 matched HIV-uninfected women (controls) enrolled in the CAPRISA 004 and 008 1% tenofovir gel trials. Pre-HIV infection, cases had significantly higher genital IgM (4.13; IQR, 4.04–4.19) compared to controls (4.06; IQR, 3.90–4.20; p = 0.042). More than one-quarter of cases (27%) had GI compared to just over one-tenth (12%) in controls. Significantly higher IgG1, IgG3, IgG4 and IgM (all p < 0.05) were found in women stratified for GI compared to women without. Adjusted linear mixed models showed several pro-inflammatory, chemotactic, growth factors, and adaptive cytokines significantly correlated with higher titers of IgM, IgA and IgG subclasses (p < 0.05). The strong and significant positive correlations between mucosal antibodies and markers of GI suggest that GI may impact mucosal antibody profiles. These findings require further investigation to establish a plausible biological link between the local inflammatory milieu and its consequence on these genital antibodies.
Highlights
Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching
No significant differences were found between cases and controls with respect to age, education, relationship status, condom use, lifetime number of partners, Herpes simplex virus-2 (HSV-2) positivity at time of study enrolment (Table 1)
Age of sexual debut was significantly lower in cases [median 17 years; interquartile range (IQR), 16–18 years] compared to controls and (18; interquartile ranges (IQR), 16–19; p = 0.008)
Summary
Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching. We investigated the impact of GI, pre-HIV infection, on antibody isotypes and IgG subclasses in the female genital tract. Pre-HIV infection, cases had significantly higher genital IgM (4.13; IQR, 4.04–4.19) compared to controls (4.06; IQR, 3.90–4.20; p = 0.042). In the RV144 trial vaccinees, circulating Env V1-V2 IgG correlated with lower HIV-1 risk through enhanced ADCC, ADCP and complement a ctivation[19,20] Whether these antibodies transduced from the circulation to the mucosal compartment to confer protection remains undefined. These findings underscore the importance of both locally and/or transduced antibody responses which may help to mitigate HIV infections
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