Plasma extracellular vesicles in people living with HIV and type 2 diabetes are related to microbial translocation and cardiovascular risk

HIV and type 2 diabetes (T2D) are both associated with gut microbiota alterations, low-grade endotoxemia and increased cardiovascular risk. We investigated the potential role of plasma extracellular vesicles (EVs) in relation to these processes. Plasma EVs were isolated by size exclusion chromatography in fasting individuals with HIV and T2D (n = 16), T2D only (n = 14), HIV only (n = 20) or healthy controls (n = 19), and characterized by transmission electron microscopy, western blot, nanoparticle tracking analysis and quantitative proteomics. The findings were compared to gut microbiota alterations, lipopolysaccharide levels and cardiovascular risk profile. Individuals with concomitant HIV and T2D had higher plasma EV concentration, which correlated closely with plasma lipopolysaccharides, triglycerides and Framingham score, but not with gut microbiota alterations. Proteomic analyses identified 558 human proteins, largely related to cardiometabolic disease genes and upstream regulation of inflammatory pathways, including IL-6 and IL-1 beta, as well as 30 bacterial proteins, mostly from lipopolysaccharide-producing Proteobacteria. Our study supports that EVs are related to microbial translocation processes in individuals with HIV and T2D. Their proteomic content suggests a contributing role in low-grade inflammation and cardiovascular risk development. The present approach for exploring gut-host crosstalk can potentially identify novel diagnostic biomarkers and therapeutic targets.Peer reviewe

Pelaksanaan Perjanjian Dana Pensiun Lembaga Keuangan Berdasarkan Undang-undang Nomor 11 Tahun 1992 Tentang Dana Pensiun

PT. Bank Negara Indonesia (Persero) Tbk. One is the founder and Pension Fund. The problems discussed in this research is how the implementation of the agreement, PT Pension Fund. Bank Negara Indonesia (Persero) in the main branches of Surakarta and legal consequences in case of breach of contract committed by one of the parties in the implementation of the agreement, PT Pension Fund. Bank Negara Indonesia (Persero) Tbk. The goal is to determine the implementation of the agreement, PT Pension Fund. Bank Negara Indonesia (Persero) Tbk in the main branches of Surakarta and legal consequences in case of breach of contract committed by one of the parties in the implementation of the agreement, PT Pension Fund. Bank Negara Indonesia (Persero).mplementation of the agreement, PT Pension Fund. Bank Negara Indonesia (Persero) started since reaching an agreement between the parties known of the existence of participant\u27s signature on the membership application form and ending at the time of payment of pension benefits, either died or moved to another Pension Fund. In the event of default of the parties, the legal consequences for the Pension Fund is responsible for the harm done, whereas for participants who violate the agreement in the agreement then the agreement is declared null and void. In addition to the settlement of defaults can be settled amicably or through the Indonesian National Board of Arbitration (BANI)

No evidence of a synergistic effect of HIV infection and diabetes mellitus type 2 on fat distribution, plasma adiponectin or inflammatory markers

Background Altered fat distribution and chronic inflammation are found in both persons living with HIV (PLWH) and persons with diabetes mellitus type 2 (DM2) and are known risk factors for cardiovascular diseases (CVD). We aimed to investigate if a synergistic effect of HIV infection and DM2 was found on fat distribution and inflammation. Methods A cross-sectional study was performed including PLWH with HIV RNA < 200 copies/mL (18 with DM2 (HIV + DM2+), 18 without DM2 (HIV + DM2-)) and controls (19 with DM2 (controls with DM2) and 25 without DM2 (healthy controls). We measured fat distribution using dual-energy X-ray absorptiometry scan. Plasma concentrations of adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF- α) and soluble CD14 (sCD14) was measured using snap-frozen plasma. Results HIV + DM2+ and HIV + DM2- had comparable trunk/limb fat ratio. In contrast, HIV + DM2+ had a higher trunk/ limb fat ratio than controls with DM2 and healthy controls (p = 0.013 and p < 0.001, respectively). However, HIV + DM2+ and controls with DM2 had comparable amount of trunk fat mass (kg) (p = 0.254). A lower concentration of plasma adiponectin and higher concentration of IL-6 was found in HIV + DM2+ than in HIV + DM2-(p = 0.037 and p = 0.039) and in healthy controls (p = 0.001 and p = 0.012). In contrast, plasma adiponectin and IL-6 concentrations were comparable in HIV + DM2+ and controls with DM2 (p = 0.345 and p = 0.825). Concentration of sCD14 was comparable in HIV + DM2+ and HIV + DM2–(p = 0.850), but elevated in HIV + DM2+ compared to controls with DM2 (p < 0.001) and healthy controls (p = 0.007). No statistical interactions were found between HIV infection and DM2 for any of the depending variables. Conclusion A synergistic effect of HIV and DM2 was not found for any of the outcomes. However, HIV + DM2+ had features related to both HIV infection and DM2 with a high trunk/limb ratio, high trunk fat mass, low concentration of plasma adiponectin and elevated concentrations of IL-6 and sCD14. This could contribute to elevated risk of CVD

Soluble T-Cell Immunoglobulin Mucin Domain-3 Is Associated With Hepatitis C Virus Coinfection and Low-Grade Inflammation During Chronic Human Immunodeficiency Virus Infection

Abstract Background In well treated human immunodeficiency virus infection (HIV), there is a residual immune activation and immune exhaustion that may contribute to increased risk of comorbidities. T-cell immunoglobulin mucin domain-3 (Tim-3) is an inhibitory molecule involved in HIV-associated T-cell dysfunction. The Tim-3 can be cleaved to soluble Tim-3 (sTim-3) that may serve as a soluble marker of immune exhaustion. Methods We measured sTim-3 with enzyme-linked immunosorbent assay DuoSets in a cross-sectional cohort of 1010 people with HIV (PWH) on antiretroviral therapy (ART), and 76 controls from the Copenhagen Co-Morbidity in HIV Infection (COCOMO) study, and in a longitudinal cohort of 60 PWH before and during ART. Results In the cross-sectional cohort, levels of sTim-3 were elevated in PWH on ART compared with controls, especially in hepatitis C virus (HCV)-coinfected individuals, and were associated with HCV viremia and inflammation. In the longitudinal cohort, pretreatment sTim-3 correlated with HIV viral load and decreased after ART initiation. Pretreatment sTim-3 correlated inversely with CD4 counts, but it did not predict immunological response in multivariable analyses. Conclusions Levels of sTim-3 decreased after ART initiation. In a cross-sectional cohort, levels of sTIM-3 were higher in PWH than in controls and were independently associated with HCV coinfection and high-sensitivity C-reactive protein, representing a potential link between immune exhaustion, inflammation, and risk of comorbidities

CCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries

Objectives: To evaluate the performance of selected host immunological biomarkers in differentiating tuberculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries. Design: Participants with TB disease (N = 85) and LTBI (N = 150) were recruited from prospective cohorts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status. Results: Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1+RANTES+CRP+MIP-1α) derived from a training set (n = 155) differentiated TB disease from LTBI in the test set (n = 67) with a sensitivity of 56.0% (95% CI, 34.9–75.6) and a specificity of 85.7% (95% CI, 71.5–94.6). A 5-marker signature derived from the HIV uninfected group (CCL1+RANTES+MIP-1α+procalcitonin+IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a specificity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1+TNF-α) identified in HIV-infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respectively in the test set. Conclusions: Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration

Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis

Introduction: Residual immune dysfunctions, resembling those that occur during normal aging, may persist even in well-treated people with HIV (PWH), and accelerated aging has been proposed. We aimed to determine if HIV infection is an independent risk factor for T-cell immune dysfunctions including increased immune activation, senescence and apoptosis. Moreover, in PWH we aimed to identify the associations between age and immune activation, senescence and apoptosis. Materials and Methods: We included 780 PWH with suppressed viral replication (<50 copies/mL) and absence of hepatitis B and hepatitis C co-infection and 65 uninfected controls from the Copenhagen Co-morbidity in HIV Infection (COCOMO) Study. Flow cytometry was used to determine T-cell activation (CD38+HLA-DR+), senescence (CD28-CD57+), and apoptosis (CD28-CD95+). T-cell subsets are reported as proportions of CD4+ and CD8+ T-cells. We defined an elevated proportion of a given T-cell subset as above the 75th percentile. Regression models were used to determine the association between HIV status and T-cell subset and in PWH to determine the association between age or HIV-specific risk factors and T-cell subsets. Furthermore, an interaction between HIV status and age on T-cell subsets was investigated with an interaction term in models including both PWH and controls. Models were adjusted for age, sex, BMI, and smoking status. Results: In adjusted models a positive HIV status was associated with elevated proportions of CD8+ activated (p = 0.009), CD4+ senescent (p = 0.004), CD4+ apoptotic (p = 0.002), and CD8+ apoptotic (p = 0.003) T-cells. In PWH a 10-year increase in age was associated with higher proportions of CD4+ and CD8+ senescent (p = 0.001 and p < 0.001) and CD4+ and CD8+ apoptotic T-cells (p < 0.001 and p < 0.001). However, no interaction between HIV status and age was found. Furthermore, in PWH a CD4+/CD8+ ratio < 1 was associated with elevated proportions of T-cell activation, senescence, and apoptosis. Discussion: We found evidence of residual T-cell immune dysfunction in well-treated PWH without HBV or HCV co-infection, and age was associated with T-cell senescence and apoptosis. Our data supports that HIV infection has similar effects as aging on T-cell subsets. However, since no interaction between HIV status and age was found on these parameters, we found no evidence to support accelerated immunological aging in PWH