Genital inflammation and the risk of HIV acquisition in women

Abstract

Background: Women in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group.

Methods: Twelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1α, IL-1β, IL-6, tumor necrosis factor-α, IL-8, interferon-γ inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1α, MIP-1β), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial.

Results: HIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1β, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3-7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines.

Conclusions: Elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.

Keywords: HIV transmission; cytokine; female genital tract; inflammation.

Figure 1.

Unsupervised hierarchical clustering was used to visualize the variation in cytokine concentrations in individual women and to cluster women according to the similarities of their cytokine expression profiles (using Qlucore Omics Explorer). Women who later became human immunodeficiency virus (HIV)–infected (n = 58; blue blocks) had upregulated preinfection cervicovaginal lavage cytokine concentrations and tended to cluster together, while women who remained HIV-uninfected had lower cytokine concentrations and also clustered together (n = 58; yellow blocks). Cytokine concentrations are indicated using a color scale that ranges from green (low) through black to red (high). The dendrogram above the heat map illustrates degrees of relatedness between genital cytokine profiles evident within the various women. The dendrogram on the left-hand side of the heat map indicates relationships between the expression profiles of the analyzed cytokines across all of the women assessed in this study. Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; IP-10, interferon-γ inducible protein-10; MCP-1, monocyte chemoattractant protein-1; MIP, macrophage inflammatory protein; TNF-a, tumor necrosis factor-alpha.

Figure 2.

Identification of multivariate cytokine profiles associated with human immunodeficiency virus (HIV) infection at a later time. A, Partial least squares discriminant analysis model of all 12 cytokines classified individuals with 65% overall accuracy for classification and 63% accuracy for cross-validation (blue, remain uninfected; red, become infected). B, Latent variable 1 best separated individuals who became infected with HIV from those who remained uninfected. Cytokine loadings indicate multivariate cytokines associated with HIV infection. Since individuals who became infected with HIV clustered in the positive region of latent variable 1 (LV1) (A), cytokines positively loaded on LV1 (macrophage inflammatory protein [MIP]-1α, MIP-1β, interferon-γ inducible protein-10 [IP-10], interleukin [IL]-8, IL-1α, IL-1β, IL-6, tumor necrosis factor-alpha [TNF-α], IL-7, and IL-10) (B) are elevated in profiles of those who became infected while negative loadings (monocyte chemoattractant protein-1 [MCP-1], granulocyte macrophage colony-stimulating factor [GM-CSF]) were comparatively reduced. Logistic regression analysis indicated that higher scores on LV1 were associated with a 2.86-fold (95% confidence interval, 1.54–5.30 and P = .0009) higher odds of infection. Variable importance projection scores indicated that MIP-1α, MIP-1β, IL-8, and IP-10 were most important for classification of the 2 groups.

Figure 3.

Spearman correlations between genital tract cytokine concentrations in the same women (n = 57) at 2 time points (median 48 weeks apart [range, 8–104]). The correlation coefficient was >0.3 (P < .05) for interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, and IL-7, and these associations remained significant following adjustment for multiple comparisons. Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; IP-10, interferon-γ inducible protein-10.

Figure 4.

Cytokine concentrations in cervicovaginal lavage (CVL) samples from human immunodeficiency virus–uninfected placebo and tenofovir (TFV) gel users. CVL cytokine concentrations in women who were using placebo gel (n = 70) are indicated by blue circles; red circles indicate those of TFV gel users (n = 46). Lines indicate medians. No significant differences (P < .05) were found using Mann–Whitney U test. Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; IP-10, interferon-γ inducible protein-10; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; TNF-α, tumor necrosis factor-alpha.