interleukin-8 and Vaginitis

The presence of genital inflammatory responses and a compromised vaginal epithelial barrier have been linked to an increased risk of HIV acquisition. It is important to assure that application of candidate microbicides designed to limit HIV transmission will not cause these adverse events. We previously developed high resolution in vivo imaging methodologies in sheep to assess epithelial integrity following vaginal application of a model microbicide, however characterization of genital inflammation in sheep has not been previously possible. In this study, we significantly advanced the sheep model by developing approaches to detect and quantify inflammatory responses resulting from application of a nonoxynol-9-containing gel known to elicit vaginal irritation. Vaginal application of this model microbicide resulted in foci of disrupted epithelium detectable by confocal endomicroscopy. Leukocytes also infiltrated the treated mucosa and the number and composition of leukocytes obtained by cervicovaginal lavage (CVL) were determined by differential staining and flow cytometry. By 18h post-treatment, a population comprised predominantly of granulocytes and monocytes infiltrated the vagina and persisted through 44h post-treatment. The concentration of proinflammatory cytokines and chemokines in CVL was determined by quantitative ELISA. Concentrations of IL-8 and IL-1β were consistently significantly increased after microbicide application suggesting these cytokines are useful biomarkers for epithelial injury in the sheep model. Together, the results of these immunological assessments mirror those obtained in previous animal models and human trials with the same compound and greatly extend the utility of the sheep vaginal model in assessing the vaginal barrier and immune microenvironment.

Topics: Animals; Anti-Infective Agents; Biomarkers; Cattle; Cellular Microenvironment; Disease Models, Animal; Drug Evaluation, Preclinical; Epithelium; Female; HIV Infections; HIV-1; Humans; Immunophenotyping; Inflammation Mediators; Interleukin-1beta; Interleukin-8; Leukocytes; Nonoxynol; Vagina; Vaginitis

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.. 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.. 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.. 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.

Topics: Africa; Cervix Uteri; Chemokine CCL2; Chemokines; Cytokines; Disease Susceptibility; Female; Genital Diseases, Female; Genitalia, Female; HIV Infections; Humans; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-6; Interleukin-8; Sexually Transmitted Diseases; South Africa; Tumor Necrosis Factor-alpha; Uterine Cervicitis; Vagina; Vaginal Douching; Vaginitis; Young Adult

Cervical shedding of HIV-1 DNA may influence HIV-1 sexual transmission. HIV-1 DNA was detected in 250 (80%) of 316 and 207 (79%) of 259 cervical cytobrush specimens from 56 US and 80 Kenyan women, respectively. Plasma HIV-1 RNA concentration was associated with increased HIV-1 DNA shedding among US and Kenyan women. Kenyan women had higher cervicovaginal concentrations of proinflammatory interleukins (IL)-1β, IL-6, IL-8, and anti-inflammatory secretory leukocyte protease inhibitor compared with US women (all P < 0.01). HIV-1 DNA shedding was associated with increased concentrations of IL-1β and IL-6 and lower secretory leukocyte protease inhibitor among US women but not Kenyan women.

Topics: Adult; Anti-Retroviral Agents; CD4 Lymphocyte Count; Cervix Uteri; Cytomegalovirus Infections; DNA, Viral; Female; Herpes Genitalis; HIV Infections; HIV-1; Humans; Interleukin-1; Interleukin-1beta; Interleukin-8; Kenya; Middle Aged; Prospective Studies; Reproductive Tract Infections; RNA, Viral; United States; Uterine Cervicitis; Vagina; Vaginitis; Viral Load

In this cross-sectional study, 53 cervicovaginal lavage samples (CVL) from 41 women were analyzed for the chemokines interleukin-8 (IL-8), regulated-on-activation normal T-expressed and secreted (RANTES) factor, and macrophage inflammatory protein-1alpha (MIP-1alpha) by enzyme-linked immunosorbent assay (ELISA). IL-8 was detected in 81% of CVL, whereas RANTES was detected in 32%, and MIP-1alpha in 15% of the CVL. The mean levels of IL-8, RANTES, and MIP-1alpha in positive samples were 396 pg/ml, 102 pg/ml, and 34 pg/ml, respectively. IL-8 levels correlated positively with IL-1beta and IgG in a subset of CVL samples. RANTES levels correlated positively with complement protein levels. Additionally, the levels of RANTES, but not MIP-1alpha, reached levels reported in previous studies of the effects of beta chemokines to inhibit HIV replication. These results suggest that measuring chemokines in CVL specimens can provide important information regarding immune responses in the genital tract.

Topics: Cervix Uteri; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Cross-Sectional Studies; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; HIV Seronegativity; HIV Seropositivity; Humans; Interleukin-8; Macrophage Inflammatory Proteins; Papillomaviridae; Papillomavirus Infections; Therapeutic Irrigation; Tumor Virus Infections; Vagina; Vaginitis