Increased Systemic Inflammation and Gut Permeability Among Women With Treated HIV Infection in Rural Uganda.
Ontology highlight
ABSTRACT:
SUBMITTER: Siedner MJ
PROVIDER: S-EPMC6093434 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Publications
Increased Systemic Inflammation and Gut Permeability Among Women With Treated HIV Infection in Rural Uganda.
Siedner Mark J MJ Zanni Markella M Tracy Russell P RP Kwon Douglas S DS Tsai Alexander C AC Kakuhire Bernard B Hunt Peter W PW Okello Samson S
The Journal of infectious diseases 20180801 6
In a cohort of human immunodeficiency virus (HIV)-infected individuals and age- and sex-matched HIV-uninfected comparators, we assessed soluble CD14 (sCD14), sCD163, interleukin 6, intestinal fatty acid binding protein (IFAPB), and high-sensitivity C-reactive protein (hs-CRP) levels. The median age was 51 years. Among HIV-positive individuals, the median antiretroviral therapy (ART) duration was 7 years, the median CD4+ T-cell count was 433 cells/μL, and 86% had an undetectable viral load. Altho ...[more]
Similar Datasets
Project description:Novel therapeutic strategies are needed to attenuate increased systemic and gut inflammation that contribute to morbidity and mortality in chronic HIV infection despite potent antiretroviral therapy (ART). The goal of this study is to use preclinical models of chronic treated HIV to determine whether the antioxidant and anti-inflammatory apoA-I mimetic peptides 6F and 4F attenuate systemic and gut inflammation in chronic HIV. We used two humanized murine models of HIV infection and gut explants from 10 uninfected and 10 HIV infected persons on potent ART, to determine the in vivo and ex vivo impact of apoA-I mimetics on systemic and intestinal inflammation in HIV. When compared to HIV infected humanized mice treated with ART alone, mice on oral apoA-I mimetic peptide 6F with ART had consistently reduced plasma and gut tissue cytokines (TNF-α, IL-6) and chemokines (CX3CL1) that are products of ADAM17 sheddase activity. Oral 6F attenuated gut protein levels of ADAM17 that were increased in HIV-1 infected mice on potent ART compared to uninfected mice. Adding oxidized lipoproteins and endotoxin (LPS) ex vivo to gut explants from HIV infected persons increased levels of ADAM17 in myeloid and intestinal cells, which increased TNF-α and CX3CL1. Both 4F and 6F attenuated these changes. Our preclinical data suggest that apoA-I mimetic peptides provide a novel therapeutic strategy that can target increased protein levels of ADAM17 and its sheddase activity that contribute to intestinal and systemic inflammation in treated HIV. The large repertoire of inflammatory mediators involved in ADAM17 sheddase activity places it as a pivotal orchestrator of several inflammatory pathways associated with morbidity in chronic treated HIV that make it an attractive therapeutic target.
| S-EPMC8740974 | biostudies-literature
Project description:BACKGROUND:Although both chronic lung disease and HIV are inflammatory diseases common in sub-Saharan Africa, the relationship between systemic inflammation and lung function among people living with HIV (PLWH) in sub-Saharan Africa is not well described. METHODS:We measured lung function (using spirometry) and serum high sensitivity C-reactive protein, interleukin 6 (IL-6), soluble CD14 (sCD14), and soluble CD163 (sCD163) in 125 PLWH on stable antiretroviral therapy (ART) and 109 age- and sex-similar HIV-uninfected control subjects in rural Uganda. We modeled the relationship between lung function and systemic inflammation using linear regression, stratified by HIV serostatus, controlled for age, sex, height, tobacco, and biomass exposure. RESULTS:Half of subjects [46% (107/234)] were women, and the median age was 52 years (interquartile range: 48-55). Most PLWH [92% (115/125)] were virologically suppressed on first-line ART. Median CD4 count was 472 cells/mm. In multivariable linear regression models stratified by HIV serostatus, an interquartile range increase in IL-6 and sCD163 were each inversely associated with lung function (mL, 95% confidence interval) among PLWH [IL-6: forced expiratory volume in 1 second (FEV1) -18.1 (-29.1 to -7.1), forced vital capacity (FVC) -17.1 (-28.2 to -5.9); sCD163: FVC -14.3 (-26.9 to -1.7)]. High sensitivity C-reactive protein (>3 vs. <1 mg/L) was inversely associated with lung function among both PLWH and HIV-uninfected control subjects [PLWH: FEV1 -39.3 (-61.7 to -16.9), FVC -44.0 (-48.4 to -6.4); HIV-uninfected: FEV1 -37.9 (-63.2 to -12.6), FVC -58.0 (-88.4 to -27.5)]. sCD14 was not associated with lung function, and all interaction terms were insignificant. CONCLUSIONS:Macrophage activation and systemic inflammation are associated with lower lung function among PLWH on stable ART in rural Uganda. Future work should focus on underlying mechanisms and public health implications.
| S-EPMC6037568 | biostudies-literature
Project description:The aims of this study were to explore intestinal microbial composition and functionality in primary Sjögren's syndrome (pSS) and to relate these findings to inflammation, permeability and the transcription factor Forkhead box protein P3 (FOXP3) gene expression in peripheral blood. The study included 19 pSS patients and 19 healthy controls matched for age, sex, and body mass index. Fecal bacterial DNA was extracted and analyzed by 16S rRNA sequencing using an Ion S5 platform followed by a bioinformatics analysis using Quantitative Insights into Microbial Ecology (QIIME II) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Our data suggest that the gut microbiota of pSS patients differs at both the taxonomic and functional levels with respect to healthy controls. The gut microbiota profile of our pSS patients was characterized by a lower diversity and richness and with Bacteroidetes dominating at the phylum level. The pSS patients had less beneficial or commensal butyrate-producing bacteria and a higher proportion of opportunistic pathogens with proinflammatory activity, which may impair intestinal barrier function and therefore contribute to inflammatory processes associated with pSS by increasing the production of proinflammatory cytokines and decreasing the release of the anti-inflammatory cytokine IL-10 and the peripheral FOXP3 mRNA expression, implicated in the development and function of regulatory T cells (Treg) cells. Further studies are needed to better understand the real impact of dysbiosis on the course of pSS and to conceive preventive or therapeutic strategies to counteract microbiome-driven inflammation.
| S-EPMC7699261 | biostudies-literature
Project description:BackgroundHIV-exposed, uninfected (HEU) children have poorer early-life outcomes than HIV-unexposed children. The determinants of adverse health outcomes among HEU children are poorly understood but may result from chronic placental inflammation (CPI).Setting and methodsWe enrolled 176 pregnant women living with HIV (WLWH) taking antiretroviral therapy in southwestern Uganda and 176 HIV-uninfected women to compare CPI prevalence by maternal HIV serostatus. Placentas were evaluated histologically by an expert pathologist for presence of CPI, defined as chronic chorioamnionitis, plasma cell deciduitis, villitis of unknown etiology, or chronic histiocytic intervillositis. Placentas with CPI were additionally immunostained with CD3 (T cell), CD20 (B cell), and CD68 (macrophage) markers to characterize inflammatory cell profiles.ResultsWLWH and HIV-uninfected women had similar age, parity, and gestational age. Among WLWH, the mean CD4 count was 480 cells/µL, and 74% had an undetectable HIV viral load. We detected CPI in 16 (9%) placentas from WLWH and 24 (14%) from HIV-uninfected women (P = 0.18). Among WLWH, CPI was not associated with the CD4 count or HIV viral load. Villitis of unknown etiology was twice as common among HIV-uninfected women than WLWH (10 vs. 5%, P = 0.04). Among placentas with CPI, more villous inflammatory cells stained for CD3 or CD68 among HIV-uninfected women than WLWH (79% vs. 46%, P = 0.07).ConclusionsCPI prevalence did not differ by HIV serostatus. T-cell (CD3) and macrophage (CD68) markers were more prevalent in placental inflammatory cells from HIV-uninfected women. Our results do not support CPI as a leading mechanism for poor outcomes among HEU children in the antiretroviral therapy era.
| S-EPMC7668230 | biostudies-literature
Project description:The complexities of navigating pregnancy while living with HIV predispose women to additional stress. Finding ways to minimize psychosocial challenges during the perinatal period may maximize the well-being of mothers living with HIV and their children. The goal of this study was to explore psychosocial challenges experienced by women living with HIV (WLWH) during pregnancy and the postpartum. We conducted individual in-depth interviews with 20 WLWH recruited from an HIV treatment cohort study in Mbarara, Uganda as part of a larger study exploring perinatal depression. We conducted content analyses to identify themes related to challenges of WLWH during pregnancy and the postpartum. Participants had a median age of 33 years [IQR: 28-35], a median of 3 living children [IQR: 2-5], and 95% had achieved HIV-RNA suppression. Challenges were organized around the following themes: HIV -related stigma from health professionals, HIV status disclosure dilemma, unintended pregnancy and intimate partner violence, HIV and environmental structural barriers and distress and fear related to maternal and child health. Stigma centered on discrimination by health care professionals and personal shame associated with being pregnant as a WLWH. This led to difficulty engaging in HIV care, particularly when coupled with structural barriers, such as lack of transportation to clinic. Participants experienced intimate partner violence and lacked support from their partners and family members. Distress and fear about the health and uncertainty about the future of the unborn baby due to maternal deteriorating physical health was common. The perinatal period is a time of stress for WLWH. Challenges experienced by WLWH may compromise successful engagement in HIV care and may reduce quality of life for women and their children. Strategies aimed at alleviating the challenges of WLWH should involve the larger structural environment including partners, family and community member as well as policy makers, funders and program implementers to work together for the common cause. These consolidated efforts may not only lower the risk of psychological distress but has potential to create long lasting solutions to benefit the wider community.
| S-EPMC5411062 | biostudies-literature
Project description:BackgroundStigma is a formidable social structural barrier to HIV testing, and yet the effect of stigma on HIV testing is rarely examined at the community level. We aimed to examine the geospatial relationships of perceived HIV stigma and HIV testing among men and women living in rural Uganda.MethodsWomen and men (aged ≥18 years or emancipated minor) residing in rural areas of Uganda who self-identified as HIV negative completed interviews that included measures of HIV testing history and how participants perceived HIV stigma. We used geospatial cluster analyses to identify areas of higher perceived stigma and lower perceived stigma and the geographical dispersion of these areas. We used Poisson regression models stratified by gender to test individual-level and community-level perceived stigma in relation to frequency of HIV testing in the previous 2 years.FindingsBetween Nov 25, 2015, and May 26, 2017, we interviewed 9740 participants (4359 [45%] men and 5381 [55%] women]), among whom 940 (9%) had never been tested for HIV, and among those who had been tested, 1131 (12%) had not been tested in the previous 2 years. Men (3134 [72%] of 4359) were less likely to have been tested in the past 2 years than women (4535 [84%] of 5381) were (p<0·001). We used Poisson regression models, reporting B coefficients, to test study hypotheses regarding the effects of individual-level and community-level stigma on HIV testing frequency counts. Multilevel modelling showed that women showed significant individual-level (B=-0·173, p<0·001) and community-level (B=-0·223, p<0·001) associations between lower stigma predicting higher rates of HIV testing. For men, lower individual-level perceived stigma was also associated with higher testing frequency (B=-0·030, p=0·018), whereas higher community-level perceived stigma was associated with higher testing frequency (B=0·077, p=0·008).InterpretationOur results suggest that perceived HIV stigma at the community level exerts a differential influence on testing for women and men. HIV testing campaigns that are targeted to men and women in rural Uganda will require gender tailoring to fit local contexts.FundingUS National Institute of Mental Health.
| S-EPMC9706443 | biostudies-literature
Project description:Background Although ≈70% of the world's population of people living with HIV reside in sub-Saharan Africa, there are minimal prospective data on the contributions of HIV infection to atherosclerosis in the region. Methods and Results We conducted a prospective observational cohort study of people living with HIV on antiretroviral therapy >40 years of age in rural Uganda, along with population-based comparators not infected with HIV. We collected data on cardiovascular disease risk factors and carotid ultrasound measurements annually. We fitted linear mixed effects models, adjusted for cardiovascular disease risk factors, to estimate the association between HIV serostatus and progression of carotid intima media thickness (cIMT). We enrolled 155 people living with HIV and 154 individuals not infected with HIV and collected cIMT images at 1045 visits during a median of 4 annual visits per participant (interquartile range 3-4, range 1-5). Age (median 50.9 years) and sex (49% female) were similar by HIV serostatus. At enrollment, there was no difference in mean cIMT by HIV serostatus (0.665 versus 0.680 mm, P=0.15). In multivariable models, increasing age, blood pressure, and non-high-density lipoprotein cholesterol were associated with greater cIMT (P<0.05), however change in cIMT per year was also no different by HIV serostatus (0.004 mm/year for HIV negative [95% CI, 0.001-0.007 mm], 0.006 mm/year for people living with HIV [95% CI, 0.003-0.008 mm], HIV×time interaction P=0.25). Conclusions In rural Uganda, treated HIV infection was not associated with faster cIMT progression. These results do not support classification of treated HIV infection as a risk factor for subclinical atherosclerosis progression in rural sub-Saharan Africa. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT02445079.
| S-EPMC8477876 | biostudies-literature
Project description:Comprehensive HIV treatment and care makes it safer for women living with HIV (WLWH) to have the children they desire, partly through provision and appropriate use of effective contraception. However, nearly one third of WLWH in-care in a large Ugandan cohort became pregnant within 3 years of initiating ART and half of these incident pregnancies (45%) were unplanned. We therefore describe future pregnancy plans and associated factors among postpartum WLWH in rural southwestern Uganda in order to inform interventions promoting postpartum contraceptive uptake. This analysis includes baseline data collected from adult WLWH enrolled into a randomized controlled trial to evaluate the effect of family planning support versus standard of care at 12 months postpartum in southwestern Uganda. Enrolled postpartum WLWH completed an interviewer-administered questionnaire at enrolment. Among 320 enrolled women, mean age, CD4 count, and duration on ART was 28.9 (standard deviation [SD] 5.8) years, 395 cells/mm3 (SD = 62) and 4.6 years (SD = 3.9), respectively. One-hundred and eighty nine (59%) of women reported either personal (175, 55%) or partner (186, 58%) desire for more children in the next 2 years. Intentions to have more children was strongly associated with partner's desire for more children (AOR = 31.36; P < 0.000), referent pregnancy planned (AOR = 2.69; P = 0.050) and higher household income > 150,000 Shs per month (AOR = 1.37; P = 0.010). Previous use of modern contraception (AOR = 0.07; P = 0.001), increasing age (AOR = 0.34; P = 0.012), having > 2 own children living in a household (AOR = 0.42; P = 0.021) and parity > 2 (AOR = 0.59; P = 0.015) were associated with reduced odds of pregnancy intention. Our findings highlight the role male partners play in influencing pregnancy intentions postpartum and the importance of engaging men in sexual and reproductive health counselling about child spacing for the health of women, children, and families. This should be addressed alongside key individual-level social, demographic, economic and structural factors within which couples can understand risks of unplanned pregnancies and access effective contraceptive methods when they need or want them.
| S-EPMC6486443 | biostudies-literature
Project description:Recent findings suggest an association between obesity, loss of gut barrier function and changes in microbiota profiles. Our primary objective was to examine the effect of caloric restriction and subsequent weight reduction on gut permeability in obese women. The impact on inflammatory markers and fecal microbiota was also investigated. The 4-week very-low calorie diet (VLCD, 800?kcal/day) induced a mean weight loss of 6.9?±?1.9?kg accompanied by a reduction in HOMA-IR (Homeostasis model assessment-insulin resistance), fasting plasma glucose and insulin, plasma leptin, and leptin gene expression in subcutaneous adipose tissue. Plasma high-molecular weight adiponectin (HMW adiponectin) was significantly increased after VLCD. Plasma levels of high-sensitivity C-reactive protein (hsCRP) and lipopolysaccharide-binding protein (LBP) were significantly decreased after 28 days of VLCD. Using three different methods, gut paracellular permeability was decreased after VLCD. These changes in clinical parameters were not associated with major consistent changes in dominant bacterial communities in feces. In summary, a 4-week caloric restriction resulted in significant weight loss, improved gut barrier integrity and reduced systemic inflammation in obese women.
| S-EPMC5607294 | biostudies-literature
Project description:AimTo investigate markers of systemic inflammation in pre- and postmenopausal women and identify possible predictors of systemic inflammation with menopause.MethodsCross-sectional study of 69 healthy women between 45- and 60 years. Blood samples were collected to assess leukocyte subsets and plasma cytokines. MRI and DXA scans were performed to assess body composition. Through uni- and multivariate analyses, follicle-stimulating hormone (FSH), visceral fat mass and age were evaluated as predictors of systemic inflammation in relation to menopause.ResultsPostmenopausal women tended to have higher leukocyte counts (5.4 x109 vs. 4.9 x109 cells/l, p = 0.05) reflected in increased total lymphocytes (1.8 x109 vs. 1.6 x109 cells/l, p = 0.01) and monocytes (0.5 x109 vs. 0.4 x109 cells/l, p = 0.02), compared to premenopausal women. Increased visceral fat mass was a strong predictor of high leukocyte subsets. Postmenopausal women had higher plasma TNF-α (2.24 vs. 1.91 pg/ml, p = 0.01) and IL-6 (0.45 vs. 0.33 pg/ml, p = 0.004) compared to premenopausal women and high FSH was a significant predictor of increased plasma TNF-α, IL-1β and IL-6. Menopause was further associated with increased T-cells (1,336 vs. 1,128 cells/μl, p = 0.04) reflected in significantly higher counts of exhausted-, senescent-, and memory CD4+ T-cell subsets.ConclusionsMenopause is associated with increased systemic inflammation as well as exhausted- and senescent T-cells. We suggest, that both increased visceral fat mass and declining sex hormone levels might contribute to postmenopausal systemic inflammation and calls for further large-scale studies to confirm these findings.
| S-EPMC7310708 | biostudies-literature