Abstract
BackgroundHigh concentrations of pro-inflammatory cytokines have been previously observed in the genital fluids of women enrolled in microbicide trials and may explain observed increased HIV transmission in some of these trials. Although the longitudinal nature of these studies allows within-subject comparisons of post-product levels to baseline levels, the fact that the physiologic variations of these cytokines and other markers of immune activation are not fully defined in different populations, makes it difficult to assess changes that can be directly attributed to microbicide use as opposed to other biological and behavioural factors.MethodsCervicovaginal lavage samples were collected from 30 healthy Caucasian and assayed for concentrations of ten cytokines/chemokines, total protein content and two antimicrobial proteins using a multiplex immunoassay and ELISA. Cellular markers were characterized by flow cytometry on mononuclear cells collected from the endocervix using flocked swabs. Bacterial quantification was performed using quantitative PCR.ResultsEctopy, menstrual cycle phase, prostate-specific antigen and presence of leucocytes in endocervical cells' supernatant were associated with the concentrations of cyto-/chemokines in cervicovaginal secretions. Approximately 3% of endocervical cells collected were monocytes of which a median of 52% (SD = 17) expressed both CD4 and CCR5 markers. Approximately 1% of the total cells were T-cells with a median of 61% (SD = 10) CD4 and CCR5 expression. Around 5% of the monocytes and 16% of the T-cells expressed the immune activation marker HLA-DR. Higher percentages of T-cells were associated with greater quantities of IL-1RA, GM-CSF and elafin.ConclusionWe demonstrate the presence of selected soluble and cellular immune activation markers and identify their predictors in the female genital tract of healthy women. Future clinical trials should consider ectopy, sexual activity, menstrual cycle phase and presence of bacterial species as possible confounders when evaluating the possible inflammatory effects of microbicide compounds.
Highlights
In the HIV prevention campaign, safe and effective anti-HIV microbicides would offer a discrete protection option when applied vaginally by women before and/or after sexual intercourse and rectally by men who have sex with men (MSM)
It was postulated that the increased infection risk could have been partially due to microbicide-induced mucosal inflammation that results in attraction and activation of CD4+ immune cells, which are prime targets for HIV infection
We modelled analyte concentrations based on presence of ectopy, recent sexual activity as determined by prostate-specific antigen (PSA) detection, menstrual cycle phase, haemoglobin presence, leucocyte presence as well as the presence of specific bacteria in the vaginal cavity and percentages of cervical cellular markers
Summary
In the HIV prevention campaign, safe and effective anti-HIV microbicides would offer a discrete protection option when applied vaginally by women before and/or after sexual intercourse and rectally by men who have sex with men (MSM). Recent success with the CAPRISA 004 tenofovir gel trial that conferred 39% protection against HIV infection in sexually active women in South Africa [1] provided proof of concept and a much needed impetus in the field of anti-HIV microbicide development a subsequent study in a different population (VOICE) failed to show effectiveness of the vaginal tenofovir gel [2]. Clinical trials with first generation vaginal microbicide compounds including surfactants and entry/fusion inhibitors either showed no effectiveness or resulted in an increased risk of HIV infection in the subjects who used them they had proven antiviral activity in vitro [5,6,7]. The longitudinal nature of these studies allows within-subject comparisons of post-product levels to baseline levels, the fact that the physiologic variations of these cytokines and other markers of immune activation are not fully defined in different populations, makes it difficult to assess changes that can be directly attributed to microbicide use as opposed to other biological and behavioural factors
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