Impact of injectable hormonal contraceptives on innate immune environment in the genital tract in women at high risk for HIV-1 infection.

Doctor of Philosophy in Virology. University of KwaZulu-Natal, Medical School 2015.Abstract available in PDF file

Characterization of nucleoside reverse transcriptase inhibitor-associated mutations in the RNAse H region of HIV-1 subtype c infected individuals.

CAPRISA, 2017.Abstract available in pdf

Semen IgM, IgG1, and IgG3 Differentially Associate With Pro-Inflammatory Cytokines in HIV-Infected Men

Genital inflammation significantly increases the risk for HIV infection. The seminal environment is enriched in pro-inflammatory cytokines and chemokines. Here, we investigated the interplay between semen cytokines and humoral immunity to understand whether the characteristics of semen antibodies are associated with genital inflammation. In 36 HIV-infected and 40 HIV-uninfected mens' semen, HIV-specific antibodies (gp120, gp41, p66, and p24), immunoglobulin (Ig) subclasses, isotypes and cytokines, using multiplex assays, were measured. Semen IgG1, IgG3, and IgM were significantly higher in HIV-infected compared to HIV-uninfected men (p < 0.05). In HIV-uninfected men, pro-inflammatory cytokines IL-6, IL-8, and MCP-1 significantly correlated with IgG1 and total IgG (IgG1+IgG2+IgG3+IgG4) (both r≥0.55; p≤0.001). Total IgG in HIV-infected men correlated to HIV-specific antibodies in the semen irrespective of antiretroviral (ARV) use. In HIV-infected, ARV-treated men, p66 and gp41-specific antibodies were inversely correlated with IL-6 and MIP-1α (both r≥−0.65, p≤0.03). In HIV-infected, ARV-naïve men, p24 and gp120-specific antibodies correlated significantly with pro-inflammatory TNF-α (r≥0.44, p≤0.03), while p24 antibodies correlated significantly with chemokine MIP-1β (r = 0.45; p = 0.02). Local cytokines/chemokines were associated with the mucosal-specific Ig subclasses which likely effect specific antibody functions. Together, these data inform on mucosal-specific immunity that may be elicited in the male genital tract (MGT) in future vaccines and/or combination HIV prevention strategies

Modulation of female genital tract-derived dendritic cell migration and activation in response to inflammatory cytokines and toll-like receptor agonists.

CAPRISA, 2016.Abstract available in pdf

Recent Semen Exposure Impacts the Cytokine Response and Bacterial Vaginosis in Women

BackgroundThe presence of semen in the vagina from unprotected sex may influence the immune and microbial environment of the female genital tract. Inflammatory cytokine concentrations and BV-associated bacteria in female genital secretions may influence HIV risk, although the effect of recent sexual intercourse on incident BV and the cytokine milieu of cervicovaginal secretions has rarely been measured in previous studies. Here, we investigated the extent to which partner semen impacts the cytokine response and incident BV.MethodsAt baseline, we assessed the recency of semen exposure in menstrual cup supernatants by quantifying prostate specific antigen (PSA) levels using ELISA in 248 HIV-uninfected women at high risk for HIV infection. Luminex was used to measure 48 cytokines in menstrual cup supernatants and vaginal swabs to diagnose BV by Nugent score. Point-of-care screening for Chlamydia trachomatis and Neisseria gonorrhoeae was conducted using GeneXpert while OSOM was used for Trichomonas vaginalis detection. Multivariable models, adjusted for age, sexually transmitted infections, BV, current contraception use and condom use, were used to assess the impact of semen exposure on biomarkers of inflammation and BV.ResultsPresence of PSA, indicating recent semen exposure within 48 hours prior to sampling, was observed in menstrual cup supernatants of 17% (43/248) of women. Of these women, 70% (30/43) had self-reported condom use at their last sex act and 84% (36/43) had BV (Nugent score >7). PSA presence was significantly associated with prevalent BV (Relative Risk (RR), 2.609; 95% Confidence Interval (CI), 1.104 - 6.165; p = 0.029). Furthermore, women with detectable PSA had high median concentrations of macrophage inflammatory protein- beta (MIP-1α, p=0.047) and low median concentration of the stem cell growth factor beta (SCGF-β, p=0.038) compared to those without PSA.ConclusionA degree of discordance between self-reports of consistent condom use and PSA positivity was observed. There was also evidence of a relationship between recent semen exposure, BV prevalence and altered cytokine concentrations. These findings suggest that PSA, as a semen biomarker, should be taken into consideration when investigating biological markers in the female genital tract and self-reported condom use in studies on reproductive and sexual health

Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health

BACKGROUND: Cervicovaginal bacterial communities composed of diverse anaerobes with low Lactobacillus abundance are associated with poor reproductive outcomes such as preterm birth, infertility, cervicitis, and risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Women in sub-Saharan Africa have a higher prevalence of these high-risk bacterial communities when compared to Western populations. However, the transition of cervicovaginal communities between high- and low-risk community states over time is not well described in African populations. RESULTS: We profiled the bacterial composition of 316 cervicovaginal swabs collected at 3-month intervals from 88 healthy young Black South African women with a median follow-up of 9 months per participant and developed a Markov-based model of transition dynamics that accurately predicted bacterial composition within a broader cross-sectional cohort. We found that Lactobacillus iners-dominant, but not Lactobacillus crispatus-dominant, communities have a high probability of transitioning to high-risk states. Simulating clinical interventions by manipulating the underlying transition probabilities, our model predicts that the population prevalence of low-risk microbial communities could most effectively be increased by manipulating the movement between L. iners- and L. crispatus-dominant communities. CONCLUSIONS: The Markov model we present here indicates that L. iners-dominant communities have a high probability of transitioning to higher-risk states. We additionally identify transitions to target to increase the prevalence of L. crispatus-dominant communities. These findings may help guide future intervention strategies targeted at reducing bacteria-associated adverse reproductive outcomes among women living in sub-Saharan Africa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01096-9

Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health (vol 9, 163, 2021)

Following the publication of the original article [1], the authors noticed a misspelling on the name of one of the co-authors. “Musie S. Ghebermichael” should read “Musie S. Ghebremichael” The original article has been updated

Inflammatory cytokine biomarkers to identify women with asymptomatic sexually transmitted infections and bacterial vaginosis who are at high risk of HIV infection.

CAPRISA, 2016.Abstract available in pdf

Lower concentrations of chemotactic cytokines and soluble innate factors in the lower female genital tract associated with the use of injectable hormonal contraceptive.

CAPRISA, 2015.Abstract available in pdf