Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis ...and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.
Background. Bacterial vaginosis (BV) is characterized by low abundance of Lactobacillus species, high pH, and immune cell infiltration and has been associated with an increased risk of human ...papillomavirus (HPV) infection. We molecularly assessed the cervicovaginal microbiota over time in human immunodeficiency virus (HIV)-infected and HIV-uninfected women to more comprehensively study the HPV-microbiota relationship, controlling for immune status. Methods. 16S ribosomal RNA gene amplicon pyrosequencing and HPV DNA testing were conducted annually in serial cervicovaginal lavage specimens obtained over 8-10 years from African American women from Chicago, of whom 22 were HIV uninfected, 22 were HIV infected with a stable CD4⁺ T-cell count of >500 cells/mm³, and 20 were HIV infected with progressive immunosuppression. Vaginal pH was serially measured. Results. The relative abundances of Lactobacillus crispatus and other Lactobacillus species were inversely associated with vaginal pH (all P<.001). High (vs low) L. crispatus relative abundance was associated with decreased HPV detection (odds ratio, 0.48; 95% confidence interval, .24-.96; Ptrend = .03) after adjustment for repeated observation and multiple covariates, including pH and study group. However, there were no associations between HPV and the relative abundance of Lactobacillus species as a group, nor with Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii individually. Conclusions. L. crispatus may have a beneficial effect on the burden of HPV in both HIV-infected and HIV-uninfected women (independent of pH).
Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains ...unclear.
We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins.
Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV.
Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.
The perturbation of tryptophan (TRP) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and ...atherosclerosis remain unclear in the context of HIV infection.
We included 361 women (241 HIV+, 120 HIV-) with carotid artery plaque assessments from the Women's Interagency HIV Study, measured 10 plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolite-related gut bacteria were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. Associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression.
Although plasma kynurenic acid (KYNA) odds ratio (OR) = 1.93, 95% confidence interval (CI): 1.12-3.32 per one SD increase; P = 0.02) and KYNA/TRP OR = 1.83 (95% CI 1.08-3.09), P = 0.02 were positively associated with plaque, indole-3-propionate (IPA) OR = 0.62 (95% CI 0.40-0.98), P = 0.03 and IPA/KYNA OR = 0.51 (95% CI 0.33-0.80), P < 0.01 were inversely associated with plaque. Five gut bacterial genera and many affiliated species were positively associated with IPA (FDR-q < 0.25), including Roseburia spp ., Eubacterium spp., Lachnospira spp., and Coprobacter spp.; but no bacterial genera were found to be associated with KYNA. Furthermore, an IPA-associated-bacteria score was inversely associated with plaque OR = 0.47 (95% CI 0.28-0.79), P < 0.01. But no significant effect modification by HIV serostatus was observed in these associations.
In a cohort of women living with and without HIV infection, plasma IPA levels and related gut bacteria were inversely associated with carotid artery plaque, suggesting a potential beneficial role of IPA and its gut bacterial producers in atherosclerosis and CVD.
Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not ...always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.
Women living with HIV (WLWH) are often coinfected with
(TV), and annual screening is recommended. Our goal was to assess differences in TV prevalence at study entry and over time in enrollment ...cohorts of the Women's Interagency HIV Study.
In a multisite study, TV was diagnosed by wet mount microscopy. Prevalence was determined across four enrollment waves: 1994-1995, 2001-2002, 2011-2012, and 2013-2015. Generalized estimating equation multivariable logistic regression models assessed changes in visit prevalence across waves after controlling for HIV disease severity and other risks.
At 63,824 person-visits (3,508 WLWH and 1,262 women without HIV), TV was diagnosed by wet mount at 1979 visits (3.1%). After multivariable adjustment, HIV status was not associated with TV detection, which was more common among younger women, women with multiple partners, and irregular condom use. All enrollment waves showed a decline in TV detection over time, although
-value for trend did not reach significance for most recent waves. To explore the potential utility of screening among WLWH, we assessed rates of TV detection among women without appreciable vaginal discharge on examination. Initial TV prevalence among asymptomatic women was 3.5%, and prevalence decreased to 0.5%-1% in the most recent wave (2013-2015) (
-trend <0.0001).
In this cohort, TV rates are low among WLWH, and HIV does not increase TV risk. Screening may benefit newly diagnosed WLWH, women with risk factors, or those receiving care sporadically but is unlikely to further reduce the low rate of TV among women in care, especially older women without multiple partners. The clinical trials registration number for WIHS is NCT00000797.
Bone loss and cognitive impairment are common in women living with HIV (WLWH) and are exacerbated by menopause. Bone-derived undercarboxylated osteocalcin (ucOCN) and sclerostin appear to influence ...cognition. The current study investigated whether the circulating levels of these 2 proteins are associated with cognition in midlife WLWH and demographically similar HIV seronegative women.
Plasma samples from women enrolled in a musculoskeletal substudy within the Women's Interagency HIV Study were used to measure ucOCN and sclerostin. A neuropsychological (NP) test battery assessing executive function, processing speed, attention/working memory, learning, memory, verbal fluency, and motor function was administered within 6 months of musculoskeletal enrollment and every 2 years after (1-4 follow-up visits per participant). A series of generalized estimating equations were conducted to examine the association between biomarkers and NP performance at the initial assessment and over time in the total sample and in WLWH only. Primary predictors included biomarkers, time, and biomarker by time interactions. If the interaction terms were not significant, models were re-run without interactions.
Neither biomarker predicted changes in NP performance over time in the total sample or in WLWH. ucOCN was positively associated with executive function in the total sample and in WLWH and with motor skills in WLWH. ucOCN was negatively associated with attention/working memory in the total sample. There were no significant associations between sclerostin and NP performance.
The current study suggests an association between bone-derived ucOCN and cognition in women with and without HIV infection.
Background To identify reasons for increased atherosclerotic risk among women living with HIV (WLWH), we evaluated the associations between psychosocial risk factors (depressive symptoms, perceived ...stress, and posttraumatic stress disorder symptoms) and subclinical atherosclerosis among WLWH and HIV-negative women. Methods and Results Carotid artery focal plaque (localized intima-media thickness >1.5 mm) was measured using B-mode ultrasound imaging in 2004-2005 and 2010-2012 in the Women's Interagency HIV Study. We created psychosocial risk groups using latent class analysis and defined prevalent plaque at the final measurement. We also examined repeated semiannual depression measures with respect to focal plaque formation throughout follow-up. The associations between latent class and prevalent plaque, and between depressive symptom persistence and plaque formation, were assessed separately by HIV status using multivariable logistic regression. Among 700 women (median age 47 years), 2 latent classes were identified: high (n=163) and low (n=537) psychosocial risk, with corresponding prevalence of depression (65%/13%), high stress (96%/12%), and probable posttraumatic stress disorder (46%/2%). Among WLWH, plaque prevalence was 23% and 11% in high versus low psychosocial risk classes (adjusted odds ratio aOR, 2.12; 95% CI, 1.11-4.05) compared with 9% and 9% among HIV-negative women (aOR, 1.07; 95% CI, 0.24-4.84), respectively. New plaque formation occurred among 17% and 9% of WLWH who reported high depressive symptoms at ≥45% versus <45% of visits (aOR, 1.96; 95% CI, 1.06-3.64), compared with 9% and 7% among HIV-negative women (aOR, 0.82; 95% CI, 0.16-4.16), respectively. Conclusions Psychosocial factors were independent atherosclerotic risk factors among WLWH. Research is needed to determine whether interventions for depression and psychosocial stress can mitigate the increased risk of atherosclerosis for WLWH.
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