Browsing by Author "Jewanraj, Janine."

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The impact of semen exposure on the immune and microbial environments of the female genital tract.
(2021) Jewanraj, Janine.; Liebenberg, Lenine Julie.; Ngcapu, Sinaye.
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.
Investigation of multiple concurrent Human papillomavirus infections, oncogenicity, and STI co-infection as risk factors for Human immunodeficiency virus infection.
(2017) Jewanraj, Janine.; Liebenberg, Lenine Julie.; Archary, Derseree.
Background: Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs) globally and a necessary factor for cervical cancer development. While HPV infection has been associated with increased Human immunodeficiency virus (HIV) risk, the underlying mechanisms remain unclear. Since STIs upregulate cytokine production and immune cell recruitment, and reduce epithelial barrier integrity, this study investigated whether the immune responses associated with HPV infection contribute to a genital immune environment conducive to an increased risk of HIV infection. Methods: This study included a baseline assessment of 167 HIV negative women participating in the CAPRISA 008 trial. The Roche Linear Array was used to detect the presence of 37 HPV genotypes in cervicovaginal lavage (CVL) pellets. The concentrations of 48 cytokines and 9 matrix metalloproteinases (MMPs) were assessed in matching CVL supernatants by multiplex ELISA. The frequencies of activated or proliferating T cells, NK cells, and of HIV target cells were assessed on cervical cytobrush-derived specimens by flow cytometry. Multiplex PCR was conducted to determine infection with common discharge-associated STIs. Results: The study demonstrated a 50.8% HPV prevalence. HPV infection was associated with younger age, older male partners, not living with a regular partner, and higher parity. HPV infection was also associated with greater levels of IL-5, IL-6 and G-CSF, an association otherwise masked by the inflammatory nature of other STI. Concomitant HPV/STI infection resulted in reduced concentrations of IL-6 and IL-1RA relative to HPV-STI+ women. In multivariate analyses controlling for other STI and nugent score, HPV-infected women had increased concentrations of SDF-1α (β = 0.148 pg/ml). Women with HR-HPV had higher concentrations of MCP-1 (β = 0.127 pg/ml) and IL-13 (β = 0.117 pg/ml), and greater frequencies of lymphocytes (β = 1.987 pg/ml) relative to those infected with LR-HPV. Having multiple HPV infections was associated with reduced concentrations of IL-5 (β = -0.170 pg/ml). Conclusion: While discharge-related STIs are inflammatory, a more subtle immune profile was associated with HPV infection that did not overtly relate to an increased potential for HIV risk. However, this study demonstrated an association between HR-HPV and biomarkers of inflammation, suggesting the need for longitudinal investigation to confirm a biological mechanism for the relationship between persistent HR-HPV infection and HIV acquisition.