RESUMEN
Metronidazole (MDZ) treatment failure and bacterial vaginosis (BV) recurrence rates are high among African women. This cohort study identified genital immune parameters associated with treatment response by comparing vaginal microbiota and immune cell frequencies in endocervical cytobrushes obtained from 32 South African women with symptomatic BV pre- and post-metronidazole treatment. Cervical T- and dendritic-cell subsets were phenotyped using multiparameter flow cytometry and the composition of vaginal microbial communities was characterized using 16S rRNA gene sequencing. MDZ treatment led to a modest decrease in the relative abundance of BV-associated bacteria, but colonization with Lactobacillus species (other than L. iners) was rare. At 6 and 12 weeks, MDZ-treated women had a significant increase in the frequencies of CCR5+ CD4+ T cells and plasmacytoid dendritic cells compared to the pre-treatment timepoint. In addition, MDZ non-responders had significantly higher frequencies of activated CD4 T cells and monocytes compared to MDZ responders. We conclude that MDZ treatment failure was characterized by an increased expression of activated T- and dendritic-cell subsets that may enhance HIV susceptibility. These data suggest the need to further assess the long-term impact of MDZ treatment on mucosal immune response and the vaginal microbiota.
RESUMEN
INTRODUCTION: Human papillomavirus (HPV) infection is a leading cause of cervical cancer. Although this relies on infection and persistence of HPV in epithelial cells, often occurring in the context of other sexually transmitted infections (STIs) and bacterial vaginosis (BV), data on the relationships between these and their relative effects on epithelial barrier integrity in women remain sparse. This study describes the epidemiology of HPV combined with STI and/or BV prevalence and the relative impact on matrix metalloproteinases (MMPs) among South African women. METHODS: Roche Linear Array was used for HPV genotyping in menstrual cup pellets of 243 HIV-negative women participating in the CAPRISA 083 cohort study. Vulvovaginal swabs were tested for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis using Xpert® CT/NG assay and lateral flow assay, and Gram staining was performed to diagnose BV using Nugent scoring criteria. Concentrations of 5 MMPs were measured in menstrual cup supernatants by multiplexed ELISA. Fisher's exact tests, Mann-Whitney U tests, and multivariable regression models determined associations between HPV infection, STI and/or BV, and MMP concentrations. RESULTS: HPV was prevalent in 34% of women (83/243; median 23 years, interquartile range (IQR) 21-27 years). Low-risk (lr) (71%, 59/83) and high-risk (hr)-HPV infections (54.2%, 45/83) were common. Hr-HPV was frequently detected in STI and/or BV-positive women compared to women without STIs or BV (p = 0.029). In multivariable analysis, BV was associated with increased odds of hr-HPV detection (OR: 2.64, 95%CI: 1.02-6.87, p = 0.046). Furthermore, Gardasil®9 vaccine-type strains were more frequently detected in women diagnosed with STI and/or BV (55.2%, 32/58 vs 24%, 6/25; p = 0.009). Among STI and/or BV-positive women, HPV detection was significantly associated with increased MMP-10 concentrations (b = 0.55, 95% CI 0.79-1.01; p = 0.022). CONCLUSION: Most women with hr-HPV had another STI and/or BV, emphasizing an urgent need for STI and BV screening and intensive scale-up of cervical cancer screening and HPV vaccination programmes. Furthermore, the study highlights the need for more extensive research to confirm and understand the relationship between HPV infection and barrier integrity.
Asunto(s)
Infecciones por Chlamydia , Infecciones por Papillomavirus , Enfermedades de Transmisión Sexual , Neoplasias del Cuello Uterino , Vaginosis Bacteriana , Femenino , Humanos , Vaginosis Bacteriana/epidemiología , Virus del Papiloma Humano , Prevalencia , Sudáfrica/epidemiología , Estudios de Cohortes , Detección Precoz del Cáncer , Enfermedades de Transmisión Sexual/microbiología , Chlamydia trachomatis , Metaloproteinasas de la Matriz , Infecciones por Chlamydia/epidemiologíaRESUMEN
The Centre for the AIDS Programme of Research in South Africa (CAPRISA), performs world-leading research on the epidemiology, pathogenesis, prevention and treatment of HIV/AIDS, tuberculosis, and - more recently - COVID-19. A rigorous yet supportive academic culture has nurtured the careers of many successful health sciences researchers, some of whom have worked for the organization since its inception over 20 years ago. This focus on professional development is founded on a training programme that invests heavily in the individual with the payoff of strengthening the science base for HIV and tuberculosis research in South Africa. Those selected for mentorship are typically medical students from the University of KwaZulu-Natal, adjoining the headquarters of CAPRISA in Durban. Increasingly, however, the institute attracts international fellows from partnering organizations to experience the intellectually demanding, scientifically robust, cutting-edge research environment. The purpose of this voices piece is to narrate and critically evaluate the experience from the dual perspectives of host and visitor of a research training programme undertaken by three undergraduate health sciences students from Vietnam, enrolled at VinUniversity. This was the inaugural running of what is expected to be an annual summer trip to CAPRISA by Hanoi-based medical and nursing students. The formative educational experience in best practice tackling of infectious diseases in challenging clinical contexts demonstrated the importance of investing in research placement programmes for public health impact. The exchange has inspired each student to become a future leader in seeking bold, innovative, and strategic approaches to improve global health issues in their home country.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Estudiantes de Enfermería , Humanos , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Sudáfrica , Pueblos del Sudeste Asiático , VietnamRESUMEN
Preventing new HIV infections remains a global challenge. Young women continue to bear a disproportionate burden of infection. Oral pre-exposure prophylaxis (PrEP), offers a novel women-initiated prevention technology and PrEP trials completed to date underscore the importance of their inclusion early in trials evaluating new HIV PrEP technologies. Data from completed topical and systemic PrEP trials highlight the role of gender specific physiological and social factors that impact PrEP uptake, adherence and efficacy. Here we review the past and current developments of HIV-1 prevention options for women with special focus on PrEP considering the diverse factors that can impact PrEP efficacy. Furthermore, we highlight the importance of inclusion of female scientists, clinicians, and community advocates in scientific efforts to further improve HIV prevention strategies.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Profilaxis Pre-Exposición , Humanos , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Seropositividad para VIH/tratamiento farmacológicoRESUMEN
Several soluble cytokines have been associated with microbicide-induced cervicovaginal inflammation, non-optimal vaginal microbiota, and risk of HIV acquisition. Many of these biomarkers are used in preclinical assays to estimate the safety of vaginally applied products. However, there are currently no validated biomarkers to evaluate the safety of novel vaginal products in clinical trials. This hinders the rapid and rational selection of novel products being tested in first-in-human trials. We reviewed available literature to assess how best to select and measure soluble immune markers to determine product safety in first in human clinical trials of novel vaginal products.
RESUMEN
Cervical cancer disproportionately affects women of reproductive age, with 80% of cases occurring in low- and middle-income countries. Persistent infection with high-risk human papillomavirus (HPV) genotypes has been described as the most common non-systemic biological risk factor for the development of cervical cancer. The mucosal immune system plays a significant role in controlling HPV infection by acting as the first line of host defense at the mucosal surface. However, the virus can evade host immunity using various mechanisms, including inhibition of the antiviral immune response necessary for HPV clearance. Pro-inflammatory cytokines and the vaginal microbiome coordinate cell-mediated immune responses and play a pivotal role in modulating immunity. Recently, diverse vaginal microbiome (associated with bacterial vaginosis) and genital inflammation have emerged as potential drivers of high-risk HPV positivity and disease severity in women. The potential role of these risk factors on HPV recurrence and persistence remains unclear. This article reviews the role of cellular or cytokine response and vaginal microbiome dysbiosis in the clearance, persistence, and recurrence of HPV infection.
Asunto(s)
Microbiota , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Vaginosis Bacteriana , Citocinas , Femenino , Humanos , Microbiota/genética , Vagina/microbiología , Vaginosis Bacteriana/microbiologíaRESUMEN
Genital inflammation (GI) undermines topical human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) efficacy through unknown mechanisms. Here, associations between activated endocervical CD4â +â T-cell numbers and higher deoxyadenosine triphosphate (dATP) concentrations suggest that competition for intracellular metabolites within HIV target cells may reduce the efficacy of antiretroviral-based PrEP in women with GI.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Fármacos Anti-VIH/uso terapéutico , Estudios de Casos y Controles , Desoxiadenosinas/uso terapéutico , Emtricitabina/uso terapéutico , Femenino , Genitales , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Tenofovir/uso terapéuticoRESUMEN
Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching. In women, genital inflammation (GI) significantly modifies HIV risk. However, the impact of GI on mucosal antibodies remains undefined. We investigated the impact of GI, pre-HIV infection, on antibody isotypes and IgG subclasses in the female genital tract. Immunoglobulin (Ig) isotypes, IgG subclasses and 48 cytokines were measured prior to HIV infection in cervicovaginal lavages (CVL) from 66 HIV seroconverters (cases) and 66 matched HIV-uninfected women (controls) enrolled in the CAPRISA 004 and 008 1% tenofovir gel trials. Pre-HIV infection, cases had significantly higher genital IgM (4.13; IQR, 4.04-4.19) compared to controls (4.06; IQR, 3.90-4.20; p = 0.042). More than one-quarter of cases (27%) had GI compared to just over one-tenth (12%) in controls. Significantly higher IgG1, IgG3, IgG4 and IgM (all p < 0.05) were found in women stratified for GI compared to women without. Adjusted linear mixed models showed several pro-inflammatory, chemotactic, growth factors, and adaptive cytokines significantly correlated with higher titers of IgM, IgA and IgG subclasses (p < 0.05). The strong and significant positive correlations between mucosal antibodies and markers of GI suggest that GI may impact mucosal antibody profiles. These findings require further investigation to establish a plausible biological link between the local inflammatory milieu and its consequence on these genital antibodies.
Asunto(s)
Anticuerpos/inmunología , Genitales Femeninos/inmunología , Anticuerpos Anti-VIH/inmunología , Inflamación/inmunología , Membrana Mucosa/inmunología , Adolescente , Estudios de Casos y Controles , Citocinas/inmunología , Método Doble Ciego , Femenino , Genitales Femeninos/virología , Humanos , Inmunoglobulinas/inmunología , Inflamación/virología , Membrana Mucosa/virología , Estudios Retrospectivos , Tenofovir/inmunologíaRESUMEN
The standard treatment for bacterial vaginosis (BV) with oral metronidazole is often ineffective, and recurrence rates are high among African women. BV-associated anaerobes are closely associated with genital inflammation and HIV risk, which underscores the importance of understanding the interplay between vaginal microbiota and genital inflammation in response to treatment. In this cohort study, we therefore investigated the effects of metronidazole treatment on the vaginal microbiota and genital cytokines among symptomatic South African women with BV [defined as Nugent score (NS) ≥4] using 16S rRNA gene sequencing and multiplex bead arrays. Among 56 BV-positive women, we observed short-term BV clearance (NS <4) in a proportion of women six weeks after metronidazole treatment, with more than half of these experiencing recurrence by 12 weeks post-treatment. BV treatment temporarily reduced the relative abundance of BV-associated anaerobes (particularly Gardnerella vaginalis and Atopobium vaginae) and increased lactobacilli species (mainly L. iners), resulting in significantly altered mucosal immune milieu over time. In a linear mixed model, the median concentrations of pro-inflammatory cytokines and chemokines were significantly reduced in women who cleared BV compared to pre-treatment. BV persistence and recurrence were strongly associated with mucosal cytokine profiles that may increase the risk of HIV acquisition. Concentrations of these cytokines were differentially regulated by changes in the relative abundance of BVAB1 and G. vaginalis. We conclude that metronidazole for the treatment of BV induced short-term shifts in the vaginal microbiota and mucosal cytokines, while treatment failures promoted persistent elevation of pro-inflammatory cytokine concentrations in the genital tract. These data suggest the need to improve clinical management of BV to minimize BV related reproductive risk factors.
Asunto(s)
Antibacterianos/administración & dosificación , Bacterias/efectos de los fármacos , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Metronidazol/administración & dosificación , Membrana Mucosa/efectos de los fármacos , Vagina/efectos de los fármacos , Vaginosis Bacteriana/tratamiento farmacológico , Administración Oral , Adulto , Antibacterianos/efectos adversos , Bacterias/inmunología , Bacterias/patogenicidad , Disbiosis , Femenino , Interacciones Huésped-Patógeno , Humanos , Estudios Longitudinales , Metronidazol/efectos adversos , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiología , Estudios Prospectivos , Reinfección , Sudáfrica , Factores de Tiempo , Resultado del Tratamiento , Vagina/inmunología , Vagina/metabolismo , Vagina/microbiología , Vaginosis Bacteriana/diagnóstico , Vaginosis Bacteriana/inmunología , Vaginosis Bacteriana/microbiología , Adulto JovenRESUMEN
INTRODUCTION: Semen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen-induced alterations are likely short-lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations. METHODS: We assessed stored genital specimens from 152 HIV-negative KwaZulu-Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two-year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate-specific antigen (PSA) by ELISA, whereas Y-chromosome DNA (YcDNA) detection and quantification were conducted by RT-PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA-YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T-cell frequencies were assessed in cytobrushes by flow-cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits. RESULTS: Here, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA-YcDNA+ and 67% (433/651) were PSA-YcDNA-. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV-2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier-related proteins (MMP-2, TIMP-1 and TIMP-4) and activated CD4+CCR5+HLA-DR+ T cells (ß = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA-DR+ T cells (ß = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro-inflammatory cytokines (including IL-6, TNF-α, IP-10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021). CONCLUSIONS: More recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV-associated microbes, which declined by three to fifteen days of post-exposure. Although transient, semen-induced alterations may have implications for HIV susceptibility in women.
Asunto(s)
Infecciones por VIH , Biomarcadores , Femenino , Infecciones por VIH/diagnóstico , Humanos , Inflamación/diagnóstico , Embarazo , Semen , Sudáfrica/epidemiología , VaginaRESUMEN
Background: The 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. Methods: At 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. Results: Presence 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-ß, p=0.038) compared to those without PSA. Conclusion: A 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.
Asunto(s)
Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Calicreínas/metabolismo , Antígeno Prostático Específico/metabolismo , Semen/metabolismo , Conducta Sexual , Vagina/metabolismo , Vaginosis Bacteriana/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Condones , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Prevalencia , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Autoinforme , Semen/inmunología , Factores de Tiempo , Sexo Inseguro , Vagina/inmunología , Vagina/microbiología , Vaginosis Bacteriana/epidemiología , Vaginosis Bacteriana/inmunología , Vaginosis Bacteriana/microbiología , Adulto JovenRESUMEN
In order to establish productive infection in women, HIV must transverse the vaginal epithelium and gain access to local target cells. Genital inflammation contributes to the availability of HIV susceptible cells at the female genital mucosa and is associated with higher HIV transmission rates in women. Factors that contribute to genital inflammation may subsequently increase the risk of HIV infection in women. Semen is a highly immunomodulatory fluid containing several bioactive molecules with the potential to influence inflammation and immune activation at the female genital tract. In addition to its role as a vector for HIV transmission, semen induces profound mucosal changes to prime the female reproductive tract for conception. Still, most studies of mucosal immunity are conducted in the absence of semen or without considering its immune impact on the female genital tract. This review discusses the various mechanisms by which semen exposure may influence female genital inflammation and highlights the importance of routine screening for semen biomarkers in vaginal specimens to account for its impact on genital inflammation.
Asunto(s)
Infecciones por VIH/transmisión , VIH-1/patogenicidad , Semen/virología , Vagina/virología , Vaginitis/virología , Inmunidad Adaptativa , Animales , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Inmunidad Mucosa , Masculino , Factores de Riesgo , Semen/inmunología , Vagina/inmunología , Vaginitis/inmunologíaRESUMEN
Given that heterosexual transmission of HIV across the genital mucosa is the most common route of infection in women, an in-depth understanding of the biological mechanisms associated with HIV risk in the female genital tract (FGT) is essential for effective control of the epidemic. Genital pro-inflammatory cytokines are well-described biological co-factors to HIV risk. Increased levels of pro-inflammatory cytokines in the FGT have been associated with a 3-fold higher-risk of acquiring HIV, presumably through involvement in barrier compromise and the recruitment of highly activated HIV target cells to the site of initial viral infection and replication. Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are suggested possible contributors to genital inflammation in the FGT, and this, coupled with the relationship between genital inflammation and HIV risk, underscores the importance of effective treatment of STI and BV in the promotion of women's health. In most low- and middle-income countries, STIs are treated syndromically, a practice providing rapid treatment without identifying the infection source. However, this approach has been associated with over-diagnosis and the overuse of drugs. Further, because many women with STIs are asymptomatic, syndromic management also fails to treat a vast proportion of infected women. Although several studies have explored the role of STIs and the vaginal microbiome on genital inflammation and HIV risk, the impact of STI and BV management on genital inflammation remains poorly understood. This review aimed to collate the evidence on how BV and STI management efforts affect genital inflammation and the genital microbiome in women.
Asunto(s)
Infecciones por VIH/inmunología , Microbiota/inmunología , Vagina/microbiología , Vaginosis Bacteriana/inmunología , Citocinas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Susceptibilidad a Enfermedades/microbiología , Femenino , VIH/inmunología , Infecciones por VIH/virología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Membrana Mucosa/inmunología , Membrana Mucosa/microbiología , Vagina/inmunología , Vaginosis Bacteriana/microbiologíaRESUMEN
OBJECTIVES: STIs cause inflammation that is detrimental for both HIV risk and reproductive health. We assessed the impact of point-of-care (POC) STI testing, immediate treatment and expedited partner therapy (EPT) on genital tract cytokines among a cohort of young South African women. METHODS: HIV-negative women underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) by Xpert CT/NG and OSOM TV, and for bacterial vaginosis (BV) by microscopy. Women with STIs and/or BV received immediate treatment, EPT for STIs and retested after 6 and 12 weeks. Concentrations of 48 cytokines were measured in cervicovaginal fluid at each visit using multiplex ELISA technology. The impact of STI treatment on cytokine concentrations was assessed by multivariable linear mixed models and principal component analysis. RESULTS: The study enrolled 251 women with median age of 23 years (IQR 21-27). The prevalence of CT, NG and TV were 14.3%, 4.4% and 4.0%, and 34.3% had BV. Women with STIs or BV at baseline (n=94) had significantly higher concentrations of pro-inflammatory cytokines (interleukin (IL)-1α, IL-1ß, IL-6, tumour necrosis factor (TNF)-α, TNF-ß, IL-18 and macrophage inflammatory factor (MIF)) and chemokines (IL-8, IL-16, macrophage inflammatory protein (MIP)-1α, IFN-α2, monokine induced by gamma interferon (MIG), monocyte chemoattractant protein (MCP)-3, regulated on activation normal T cell expressed and secreted and eotaxin) compared with women without (n=157). STI treatment was strongly associated with reduced concentrations of pro-inflammatory cytokines IL-6 (p=0.004), IL-1ß (p=0.013), TNF-α (p=0.018) and chemokines MIG (p=0.008) and growth-related oncogene (GRO)-α (p=0.025). A lower Nugent score was associated with a reduction in pro-inflammatory cytokines IL-1α (p=0.003), TNF-related apoptosis-inducing ligand (p=0.004), MIF (p=0.010) and IL-18 (p<0.001), but an increase in chemokines MIG (p=0.020), GRO-α (p<0.001), IP-10 (p<0.001), MIP-1ß (p=0.008) and MCP-1 (p=0.005). Principal component analysis showed differences in STI and BV-related inflammatory profiles, but that resolution restored a profile consistent with vaginal health. CONCLUSIONS: A comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk.
Asunto(s)
Citocinas/inmunología , Inflamación/inmunología , Pruebas en el Punto de Atención/normas , Infecciones del Sistema Genital/inmunología , Enfermedades de Transmisión Sexual/diagnóstico , Enfermedades de Transmisión Sexual/tratamiento farmacológico , Vaginosis Bacteriana/diagnóstico , Vaginosis Bacteriana/tratamiento farmacológico , Adolescente , Adulto , Antibacterianos/uso terapéutico , Estudios de Cohortes , Citocinas/análisis , Femenino , Humanos , Inflamación/tratamiento farmacológico , Estudios Prospectivos , Infecciones del Sistema Genital/tratamiento farmacológico , Infecciones del Sistema Genital/microbiología , Enfermedades de Transmisión Sexual/microbiología , Vagina/efectos de los fármacos , Vagina/microbiología , Adulto JovenRESUMEN
PROBLEM: Injectable hormonal contraceptives (IHC) have been associated with altered mucosal and systemic milieu which might increase HIV risk, but most studies have focused on DMPA and not NET-EN, despite the growing popularity and lower HIV risk associated with the latter in observational studies. METHOD OF STUDY: We used high-performance liquid chromatography in combination with tandem triple quadrupole mass spectrometry (HPLC-LC-MS/MS) to measure steroid hormones in plasma samples of CAPRISA004 study participants. Concentrations of 48 cytokines were measured in the cervicovaginal lavage (CVL) and plasma, and their expression was compared between participants with detectable NET-EN (n = 201) versus non-detectable IHC (n = 90). Each log10 cytokine concentration was tested as an outcome in linear-mixed models, with NET-EN detection as the main explanatory variable. Multivariable models were adjusted for potential confounders. RESULTS: In bivariate analysis, detectable NET-EN was associated with reduced cervicovaginal M-CSF (P = 0.008), GM-CSF (P = 0.025) and G-CSF (P = 0.039), and elevated levels MIF (P = 0.008), IL-18 (P = 0.011), RANTES (P = 0.005) and IL-1Rα (P < 0.001). Lower G-CSF (P = 0.011) and elevated IL-1Rα (P = 0.008) remained significant in adjusted models. Multivariable analyses of plasma samples obtained from NET-EN-detectable women showed a significant increase in IP-10 (P = 0.026) and reductions in TNF-ß (P = 0.037), RANTES (P = 0.009), and M-CSF (P < 0.001). While similar growth factor reduction in CVL was noted for both DMPA and NET-EN, similar trends were not observed for endogenous progesterone. CONCLUSIONS: Detectable NET-EN was associated with reduced growth factors in the plasma and genital tract; particularly G-CSF and M-CSF. Our results suggest that while NET-EN is not inflammatory, it may have important immunological effects.
Asunto(s)
Anticonceptivos Femeninos , Citocinas/inmunología , Noretindrona , Vagina/inmunología , Adolescente , Adulto , Cromatografía Liquida , Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Femeninos/farmacocinética , Femenino , Humanos , Noretindrona/administración & dosificación , Noretindrona/farmacocinética , Sudáfrica , Espectrometría de Masas en TándemRESUMEN
OBJECTIVES: Genital herpes simplex virus (HSV) infections are common in South Africa and worldwide. While HSV-2 is known to cause genital lesions, HSV-1 is better known to cause oral infections. Due to the global rise in genital HSV-1 infections, we aimed to compare the genital cytokine environment associated with HSV-1 and HSV-2 infections and their relation to the proinflammatory genital immune environment associated with HIV risk in African women. METHODS: HSV-1 and HSV-2 DNA were detected by quantitative real-time PCR in menstrual cup specimens collected from 251 HIV-negative women participating in the CAPRISA 083 study in Durban, South Africa. HSV shedding was defined as detection at >150 copies/mL. Forty-eight cytokines were measured in genital fluid by multiplexed ELISA, and multivariable regression models determined associations between genital cytokines and HSV DNA detection. RESULTS: HSV-1 DNA detection (24/251 (9.6%)) and shedding (13/24 (54.2%)) was more common than HSV-2 (detection in 14/251 (5.6%), shedding in 0/14). None of the women with detectable HSV had evidence of genital lesions. HSV-2 DNA detection was associated with increased interleukin (IL)-18 and decreased cutaneous T-cell attracting chemokine concentrations, but only in univariable analysis. By contrast, in both univariable and multivariable analyses, the detection of HSV-1 DNA was associated with reduced concentrations of granulocyte-colony stimulating factor, IL-7, IL-4, platelet-derived growth factor-ßß and five proinflammatory cytokines associated with HIV risk: IL-6, IL-1ß, macrophage inflammatory protein (MIP)-1α, MIP-1ß and tumour necrosis factor-α. CONCLUSIONS: That HSV-1 DNA was more commonly detected and shed than HSV-2 emphasises the need for clinical screening of both viruses, not just HSV-2 in young women. Efforts to reduce genital inflammation may need to consider implementing additional strategies to mitigate a rise in HSV replication.
Asunto(s)
Cuello del Útero/virología , Citocinas , ADN Viral/análisis , Herpes Genital/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 2/genética , Esparcimiento de Virus , Adulto , Estudios Transversales , Femenino , Humanos , Prueba de Estudio Conceptual , Reacción en Cadena en Tiempo Real de la Polimerasa , Sudáfrica/epidemiología , Adulto JovenRESUMEN
Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.
Asunto(s)
Antiinflamatorios/farmacología , Betametasona/farmacología , Infecciones por VIH/prevención & control , VIH/efectos de los fármacos , Terapia de Inmunosupresión , Antiinflamatorios/uso terapéutico , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Betametasona/uso terapéutico , Linfocitos T CD4-Positivos , Células Cultivadas , Transmisión de Enfermedad Infecciosa/prevención & control , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Humanos , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Técnicas In Vitro , Leucocitos Mononucleares/inmunología , Fitohemaglutininas , Receptores Toll-Like/agonistasRESUMEN
Long-acting injectable contraceptives have been associated with mucosal immune changes and increased HIV acquisition, but studies have often been hampered by the inaccuracy of self-reported data, unknown timing of injection, and interactions with mucosal transmission co-factors. We used mass spectrometry to quantify the plasma concentrations of injectable contraceptives in women from the CAPRISA004 study (n = 664), with parallel quantification of 48 cytokines and >500 host proteins in cervicovaginal lavage. Higher DMPA levels were associated with reduced CVL concentrations of GCSF, MCSF, IL-16, CTACK, LIF, IL-1α, and SCGF-ß in adjusted linear mixed models. Dose-dependent relationships between DMPA concentration and genital cytokines were frequently observed. Unsupervised clustering of host proteins by DMPA concentration suggest that women with low DMPA had increases in proteins associated with mucosal fluid function, growth factors, and keratinization. Although DMPA was not broadly pro-inflammatory, DMPA was associated with increased IP-10 in HSV-2 seropositive and older women. DMPA-cytokine associations frequently differed by vaginal microbiome; in non-Lactobacillus-dominant women, DMPA was associated with elevated IL-8, MCP-1, and IP-10 concentrations. These data confirm a direct, concentration-dependant effect of DMPA on functionally important immune factors within the vaginal compartment. The biological effects of DMPA may vary depending on age, HSV-2 status, and vaginal microbiome composition.
Asunto(s)
Cuello del Útero/efectos de los fármacos , Cuello del Útero/metabolismo , Anticonceptivos Femeninos/farmacocinética , Regulación de la Expresión Génica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/genética , Vagina/efectos de los fármacos , Vagina/metabolismo , Adulto , Biomarcadores , Cuello del Útero/microbiología , Cromatografía Liquida , Anticonceptivos Femeninos/administración & dosificación , Citocinas/biosíntesis , Monitoreo de Drogas , Femenino , Humanos , Microbiota , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiología , Sudáfrica , Espectrometría de Masas en Tándem , Vagina/microbiología , Adulto JovenRESUMEN
Background: Semen induces an immune response at the female genital tract (FGT) to promote conception. It is also the primary vector for HIV transmission to women during condomless sex. Since genital inflammation and immune activation increase HIV susceptibility in women, semen-induced alterations at the FGT may have implications for HIV risk. Here we investigated the impact of semen exposure, as measured by self-reported condom use and Y-chromosome DNA (YcDNA) detection, on biomarkers of female genital inflammation associated with HIV acquisition. Methods: Stored genital specimens were collected biannually (mean 5 visits) from 153 HIV-negative women participating in the CAPRISA 008 tenofovir gel open-label extension trial. YcDNA was detected in cervicovaginal lavage (CVL) pellets by RT-PCR and served as a biomarker of semen exposure within 15 days of genital sampling. Protein concentrations were measured in CVL supernatants by multiplexed ELISA, and the frequency of activated CD4+CCR5+ HIV targets was assessed on cytobrush-derived specimens by flow cytometry. Common sexually transmitted infections (STIs) and bacterial vaginosis (BV)-associated bacteria were measured by PCR. Multivariable linear mixed models were used to assess the relationship between YcDNA detection and biomarkers of inflammation over time. Results: YcDNA was detected at least once in 69% (106/153) of women during the trial (median 2, range 1-5 visits), and was associated with marital status, cohabitation, the frequency of vaginal sex, and Nugent Score. YcDNA detection but not self-reported condom use was associated with elevated concentrations of several cytokines: IL-12p70, IL-10, IFN-γ, IL-13, IP-10, MIG, IL-7, PDGF-BB, SCF, VEGF, ß-NGF, and biomarkers of epithelial barrier integrity: MMP-2 and TIMP-4; and with reduced concentrations of IL-18 and MIF. YcDNA detection was not associated with alterations in immune cell frequencies but was related to increased detection of P. bivia (OR = 1.970; CI 1.309-2.965; P = 0.001) at the FGT. Conclusion: YcDNA detection but not self-reported condom use was associated with alterations in cervicovaginal cytokines, BV-associated bacteria, and matrix metalloproteinases, and may have implications for HIV susceptibility in women. This study highlights the discrepancies related to self-reported condom use and the need for routine screening for biomarkers of semen exposure in studies of mucosal immunity to HIV and other STIs.
RESUMEN
Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2-5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence.