Plasminogen Activator Inhibitor-1 Predicts Negative Alterations in Whole-Body Insulin Sensitivity in Chronic HIV Infection

Plasminogen activator inhibitor type 1 (PAI-1), a key negative regulator of fibrinolysis, has been investigated to be one of the potential mechanisms of the development of impaired insulin sensitivity, insulin resistance, and diabetes mellitus. Because chronically stable HIV-infected individuals frequently develop abnormal glucose metabolism, including insulin resistance and diabetes mellitus, we postulated that PAI-1 could be one of the multifactorial pathogenic roles in the development of impaired insulin sensitivity and insulin resistance among chronic HIV-infected individuals. From our longitudinal cohort study, we selectively recruited chronically stable HIV-infected individuals without diagnosis of diabetes mellitus at baseline (N = 62) to analyze the correlation of baseline inflammatory cytokines, including PAI-1 and whole-body insulin sensitivity, with 2-year follow-up, as measured by Matsuda Index. We found a negative correlation between baseline PAI-1 and Matsuda Index (r = -0.435, p = .001) and a negative correlation between baseline PAI-1 and Matsuda Index at 2 years (r = -0.377, p = .005). In a linear regression model that included age, total body fat mass percentage, serum amyloid A, and family history of diabetes mellitus, PAI-1 still remained significantly associated with Matsuda Index at 2-year follow-up (β = -.397, p = .002). Our longitudinal study suggests that PAI-1 is an independent predictor of impaired insulin sensitivity among chronic HIV-infected individuals

Mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells is decreased in chronic HIV and correlates with immune dysregulation.

BackgroundCellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation.MethodsPLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels.ResultsPLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA ConclusionCI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted

Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy

BackgroundInflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT).MethodsLongitudinal study of HIV-infected subjects ≥40 years and on stable antiretroviral therapy (ART) ≥3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)) and transitional (CD14(+)CD16(-)) monocyte subsets and activated (CD38(+)HLA-DR(+)) CD8(+) T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High-resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables.ResultsWe studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm(3), and with HIV RNA ≤ 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-α (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA.ConclusionsOur findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors

Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy

BACKGROUND: Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT). METHODS: Longitudinal study of HIV-infected subjects ≥ 40 years and on stable antiretroviral therapy (ART) ≥ 3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14(++)CD16(−)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)) and transitional (CD14+CD16−) monocyte subsets and activated (CD38(+)HLA-DR(+)) CD8(+) T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over 2 years at the right common carotid artery (CIMT(CCA)) and right bifurcation (CIMT(BIF)) were outcome variables. RESULTS: We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm(3), and with HIV RNA≤50 copies/mL in 84%. Change in CIMT(BIF) correlated with log values of baseline absolute count of non-classical monocytes (r=0.37, p=0.020), and with MCP-1 (r=0.42, p=0.0024) and TNF-α (r=0.30, p=0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMT(BIF), independent of Framingham Risk Score and baseline CIMT(BIF). No correlation was noted between CD8 T-cell activation and CIMT(BIF) change. Monocyte subsets, CD8 T-cell activation and biomarker concentrations were not correlated with changes in CIMT(CCA). CONCLUSIONS: Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMT(BIF) in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors