Search

Objective: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection., Methods: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up., Results: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus , were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09-1.64] and 1.24 [1.02-1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines., Conclusions: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

Objective: To evaluate plasma acylcarnitine profiles and their relationships with progression of carotid artery atherosclerosis among individuals with and without HIV infection., Design: Prospective cohort studies of 499 HIV-positive and 206 HIV-negative individuals from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study., Methods: Twenty-four acylcarnitine species were measured in plasma samples of participants at baseline. Carotid artery plaque was assessed using repeated B-mode carotid artery ultrasound imaging in 2004-2013. We examined the associations of individual and aggregate short-chain (C2-C7), medium-chain (C8-C14) and long-chain acylcarnitines (C16-C26) with incident carotid artery plaque over 7 years., Results: Among 24 acylcarnitine species, C8-carnitines and C20 : 4-carnitines showed significantly lower levels comparing HIV-positive to HIV-negative individuals (false discovery rate adjusted P < 0.05); and C20-carnitines and C26-carnitines showed significantly higher levels in HIV positive using antiretroviral therapy than those without antiretroviral therapy (false discovery rate adjusted P < 0.05). In the univariate analyses, higher aggregated short-chain and long-chain acylcarnitine scores were associated with increased risk of carotid artery plaque [risk ratios (RRs) = 1.22 (95% confidence interval 1.02-1.45) and 1.20 (1.02-1.41) per SD increment, respectively]. The association for the short-chain acylcarnitine score remained significant [RR = 1.23 (1.05-1.44)] after multivariate adjustment (including traditional cardiovascular disease risk factors). This association was more evident in HIV-positive individuals without persistent viral suppression [RR = 1.37 (1.11-1.69)] compared with those with persistent viral suppression during follow-up [RR = 1.03 (0.76-1.40)] or HIV-negative individuals [RR = 1.02 (0.69-1.52)]., Conclusion: In two HIV cohorts, plasma levels of most acylcarnitines were not significantly different between HIV-positive and HIV-negative individuals. However, higher levels of aggregated short-chain acylcarnitines were associated with progression of carotid artery atherosclerosis.

Background: Persistent inflammation in HIV infection is associated with elevated cardiovascular disease (CVD) risk, even with viral suppression. Identification of novel surrogate biomarkers can enhance CVD risk stratification and suggest novel therapies. We investigated the potential of interleukin 32 (IL-32), a proinflammatory multi-isoform cytokine, as a biomarker for subclinical carotid artery atherosclerosis in virologically suppressed women living with HIV (WLWH). Methods and Results: Nested within the Women's Interagency HIV Study, we conducted a cross-sectional comparison of IL-32 between 399 WLWH and 100 women without HIV, followed by a case-control study of 72 WLWH (36 carotid artery plaque cases vs. 36 age-matched controls without plaque). Plasma IL-32 protein was measured by ELISA, and mRNA of IL-32 isoforms (IL-32α, β, γ, D, ε, and θ) was quantified by reverse transcription polymerase chain reaction from peripheral blood mononuclear cells. Plasma IL-32 protein levels were higher in WLWH compared with women without HIV (P = 0.02). Among WLWH, although plasma IL-32 levels did not differ significantly between plaque cases and controls, expression of IL-32 isoforms α, β, and ε mRNA was significantly higher in peripheral blood mononuclear cells from cases (P = 0.01, P = 0.005, and P = 0.018, respectively). Upregulation of IL-32β and IL-32ε among WLWH with carotid artery plaque persisted after adjustment for age, race/ethnicity, smoking, systolic blood pressure, body mass index, and history of hepatitis C virus (P = 0.04 and P = 0.045); the adjusted association for IL-32α was marginally significant (P = 0.07). Conclusions: IL-32 isoforms should be studied further as potential CVD biomarkers. This is of particular interest in WLWH by virtue of altered IL-32 levels in this population. [ABSTRACT FROM AUTHOR]

Background: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women. Setting: In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques. Methods: Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP). Results: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation. Conclusions: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Ceramides have been implicated in the pathophysiology of HIV infection and cardiovascular disease. However, no study, to our knowledge, has evaluated circulating ceramide levels in association with subclinical cardiovascular disease risk among HIV-infected individuals.Methods: Plasma levels of 4 ceramide species (C16:0, C22:0, C24:0, and C24:1) were measured among 398 women (73% HIV+) and 339 men (68% HIV+) without carotid artery plaques at baseline from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. We examined associations between baseline plasma ceramides and risk of carotid artery plaque formation, assessed by repeated B-mode carotid artery ultrasound imaging over a median 7-year follow-up.Results: Plasma levels of C16:0, C22:0, and C24:1 ceramides were significantly higher in HIV-infected individuals compared with those without HIV infection (all P<0.001), and further analysis indicated that elevated ceramide levels were associated with antiretroviral therapy use, particularly protease inhibitor use, in HIV-infected individuals (all P<0.001). All 4 ceramides were highly correlated with each other ( r=0.70-0.94; all P<0.001) and significantly correlated with total-cholesterol ( r=0.42-0.58; all P<0.001) and low-density lipoprotein cholesterol ( r=0.24-0.42; all P<0.001) levels. Of note, C16:0 and C24:1 ceramides, rather than C22:0 and C24:0 ceramides, were more closely correlated with specific monocyte activation and inflammation markers (eg, r=0.30 between C16:0 ceramide and soluble CD14; P<0.001) and surface markers of CD4+ T-cell activation. A total of 112 participants developed carotid artery plaques over 7 years, and higher levels of C16:0 and C24:1 ceramides were significantly associated with increased risk of carotid artery plaques (relative risk [95% CI]=1.55 [1.29, 1.86] and 1.51 [1.26, 1.82] per standard deviation increment, respectively; both P<0.001), after adjusting for demographic and behavioral factors. After further adjustment for cardiovascular disease risk factors and immune activation markers, these associations were attenuated but remained significant. The results were consistent between men and women and between HIV-infected and HIV-uninfected participants.Conclusions: In 2 HIV cohorts, elevated plasma levels of C16:0 and C24:1 ceramides, correlating with immune activation and inflammation, were associated with antiretroviral therapy use and progression of carotid artery atherosclerosis. [ABSTRACT FROM AUTHOR]