The impact of semen exposure on the immune and microbial environments of the female genital tract.
Abstract
Background: Semen is an immunomodulatory fluid that induces mucosal changes at the female genital
tract (FGT) for sperm survival and conception. Semen-induced alterations necessary for reproduction
may also modulate the inflammatory environment related to HIV risk in women. This thesis
investigated the impact of semen exposure on biomarkers of female genital inflammation (GI) and the
persistence of these associations over time.
Methods: Stored genital specimens were assessed from HIV-negative women participating in the
CAPRISA 008 trial. Cervicovaginal lavage (CVL) samples were screened for Y-chromosome DNA
(YcDNA) by real-time PCR as a biomarker of semen exposure within 15 days of genital sampling.
Prostate-specific antigen (PSA) detection by ELISA stratified CVLs into semen exposure within 48
hours (PSA+YcDNA+) and between 3-15 days (PSA-YcDNA+). Vaginal cytokine concentrations,
matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were assessed
in CVLs using multiplexed ELISA. Endocervical T-cell frequencies were measured in cytobrushes by
flow-cytometry. Vaginal microbes and sexually transmitted infections (STIs) were detected in
vulvovaginal swabs by PCR.
Results: Self-reported condom use as a measure of semen exposure was not associated with changes in
the FGT microenvironments. Conversely, YcDNA detection predicted significant increases in several
cytokines, barrier-related proteins, and Prevotella bivia detection (p=0.001). Since YcDNA detection
alone was not associated with the immune environment linked to HIV risk, this thesis further
investigated the contribution of more recent sex to female GI. PSA detection (semen exposure within
48 hours) was associated with higher YcDNA concentrations (p<0.0001), suggesting a relationship
between the timing of semen exposure and vaginal YcDNA concentrations after condomless sex. In
support of this, both PSA detection and higher YcDNA concentrations predicted significant increases
in several cytokines, barrier-related proteins (MMP-2, TIMP-1, TIMP-4), and higher frequencies of
activated CD4+HLA-DR+ T-cells (p=0.032) and CD4+CCR5+HLA-DR+ HIV targets (p=0.046). PSA
detection was also associated with increased detection of several bacterial vaginosis (BV)-associated
microbes and reduced Lactobacillus jensenii detection.
Conclusion: Recent semen exposure contributes to the inflammatory environment associated with HIV
risk in women. These studies highlight the need for clinical and immunological studies of STIs and their
biomedical interventions to consider semen’s contribution to the immune and microbial
microenvironments of the FGT.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.