Characterization of immunoglobulin (Ig) isotypes, IgG subclasses and cytokines in the blood and genital tracts of HIV infected and healthy women from an observational cohort study (CAPRISA 082)

Abstract

Background: Heterosexual transmission remains the dominant route of HIV infections in women. Immune responses that predict HIV acquisition during pre-exposure prophylaxis (PrEP) remain undefined. We hypothesized that increased genital tract antibodies and cytokines pre-HIV infection predict HIV acquisition in seroconverters compared to non-seroconverters irrespective of PrEP use. Methods: Plasma and Softcup specimens were collected from n=12 seroconverters (cases) and n=48 non-seroconverters (controls) in the CAPRISA 082 study at five time points. Of 12 cases-, nine took PrEP, while 29 of 48 controls took PrEP. IgG1, IgG2, IgG3, IgG4, IgM and IgA, and nine cytokines: MIP-1􀄮, MIP-1􀈕, IP-10, MCP-1, and IL-8, TNF-􀄮, IL-1􀄮, IL-1􀈕, and IL-6 pre- and post-HIV infection, were measured using multiplexed technology. Results: Baseline levels of IgG subclasses, Ig isotypes, and mucosal cytokines were similar between cases and controls. Over time within the cases, plasma IgA significantly declined, in controls, plasma IgG2, IgG3, and IgM significantly declined over time (p<0.05). In cases and controls on PrEP, plasma IgG3 trended higher compared to no PrEP (p<0.1). Relative to baseline, only within the controls, mucosal IgG1, IgG2, IgG3, IgG4, IgM, and IgA declined significantly. Mucosal IgM significantly predicted four-fold increased HIV risk (p=0.01). Eight of nine cytokines in the genital tract were significantly elevated in the cases compared to controls (all p<0.05). In cases and controls who used PrEP relative to no PrEP, IP-10 was significantly lower (p=0.04 and p=0.009). Baseline mucosal IL-8 significantly correlated with mucosal IgG1, IgG2, total IgG, and IgM (p<0.001 for all). Conclusions: Although no significant elevated genital antibodies or cytokines pre-HIV infection were found, significantly different patterns of antibodies and cytokines were observed in this cohort. Plasma IgG3, one of the most effective of the IgG􀂶s eliciting diverse antibod􀁜 functions, was increased in PrEP users. Mucosal IgM was associated with increased HIV-acquisition risk, while pleiotropic IP-10, a reported risk factor was modulated in PrEP users among cases. Collectively, these data suggest that PrEP use may modulate or preserve specific immune responses that can modify HIV risk. As PrEP uptake increases, its effect on mucosal and systemic immunity is important for informing on prevention strategies where PrEP may be given alone or in combination with HIV vaccine for added efficacy.