Genital-Systemic Chemokine Gradients and the Risk of HIV Acquisition in Women

Abstract

Background: Mucosal and systemic immune mediators have been independently associated with HIV acquisition risk, but the relationship between compartments remains unclear.

Methods: To address this, the concentrations of 12 cytokines were compared in matched plasma and cervicovaginal lavages (CVLs) from 57 HIV-positive women before their acquisition of HIV (cases) and 50 women who remained uninfected (controls) during the CAPRISA 004 trial.

Results: Although genital IP-10 concentrations were significantly higher in cases, plasma IP-10 concentrations were inversely associated with HIV risk. Comparing differences in mucosal and systemic cytokine concentrations between cases and controls, mucosa-biased gradients indicating higher cervicovaginal lavage relative to plasma concentrations were observed for all 5 chemokines in the panel. Four were significantly associated with HIV acquisition, including IP-10 (odds ratio [OR] 1.73, 95% confidence interval [CI]: 1.27 to 2.36), macrophage inflammatory protein-1β (OR 1.72, 95% CI: 1.23 to 2.40), interleukin (IL)-8 (OR 1.50, 95% CI: 1.09 to 2.05), and monocyte chemotactic protein-1 (OR 1.36, 95% CI: 1.01 to 1.83). None of the other 7 cytokines tested predicted HIV risk. Decision tree analyses confirmed this association, with gradients of IP-10, IL-8, and granulocyte-macrophage colony-stimulating factor concentrations correctly classifying 77% of HIV outcomes.

Conclusions: Our findings suggest that mucosa-biased gradients of IP-10, macrophage inflammatory protein-1β, IL-8, and monocyte chemotactic protein-1 are associated with an increased risk of HIV infection.

FIGURE 1.

Mucosal–plasma chemokine gradients in women who remained uninfected (controls; n = 50) and in HIV- women who subsequently acquired HIV (cases; n = 57) during the CAPRISA 004 trial. Intercompartmental cytokine gradients were determined by quantifying the difference between standardized cytokine concentrations of the female genital tract and blood plasma for each participant. Four of the 5 gradients associated with HIV outcome in multivariate analysis are depicted here: (A) IP-10, (B) MIP-1β, (C) IL-8, and (D) monocyte chemotactic protein-1 (MCP-1). “Positive” gradients are indicative of higher relative levels in the genital tract compared with the blood.

FIGURE 2.

Decision tree analyses to identify the most influential combinations of genital and plasma, cytokine measurements associated with HIV outcome. Cytokine concentrations determined in cases (n = 57) and controls (n = 50) were modeled to include (A) the concentrations of all 12 cytokines in genital and plasma specimens, (B) mucosal-Plasma gradients, (C) all 12 genital cytokines alone, or (D) all 12 plasma cytokines. Comparison of the (E) calibration and (F) cross-Validation errors for decision trees generated using either plasma, CVL, combined CVL and plasma, or cytokine gradients, respectively.