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Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy.

ABSTRACT: Exosomes are nanovesicles released from most cell types including immune cells. Prior studies suggest exosomes play a role in HIV pathogenesis, but little is known about exosome cargo in relation to immune responses and oxidative stress. Here, we characterize plasma exosomes in HIV patients and their relationship to immunological and oxidative stress markers. Plasma exosome fractions were isolated from HIV-positive subjects on ART with suppressed viral load and HIV-negative controls. Exosomes were characterized by electron microscopy, nanoparticle tracking, immunoblotting, and LC-MS/MS proteomics. Plasma exosomes were increased in HIV-positive subjects compared to controls, and correlated with increased oxidative stress markers (cystine, oxidized cys-gly) and decreased PUFA (DHA, EPA, DPA). Untargeted proteomics detected markers of exosomes (CD9, CD63, CD81), immune activation (CD14, CRP, HLA-A, HLA-B), oxidative stress (CAT, PRDX1, PRDX2, TXN), and Notch4 in plasma exosomes. Exosomal Notch4 was increased in HIV-positive subjects versus controls and correlated with immune activation markers. Treatment of THP-1 monocytic cells with patient-derived exosomes induced expression of genes related to interferon responses and immune activation. These results suggest that exosomes in ART-treated HIV patients carry proteins related to immune activation and oxidative stress, have immunomodulatory effects on myeloid cells, and may have pro-inflammatory and redox effects during pathogenesis.

SUBMITTER: Chettimada S

PROVIDER: S-EPMC5940833 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy.

Chettimada Sukrutha S Lorenz David R DR Misra Vikas V Dillon Simon T ST Reeves R Keith RK Manickam Cordelia C Morgello Susan S Kirk Gregory D GD Mehta Shruti H SH Gabuzda Dana D

Scientific reports 20180508 1

Exosomes are nanovesicles released from most cell types including immune cells. Prior studies suggest exosomes play a role in HIV pathogenesis, but little is known about exosome cargo in relation to immune responses and oxidative stress. Here, we characterize plasma exosomes in HIV patients and their relationship to immunological and oxidative stress markers. Plasma exosome fractions were isolated from HIV-positive subjects on ART with suppressed viral load and HIV-negative controls. Exosomes we ...[more]

PMID: 29740045

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Project description:HIV-infected patients have an increased risk of cardiovascular disease (CVD). Impaired endothelial function is an early risk factor for CVD in the general population. It is presumed that HIV infection is associated with impaired endothelial function, but results have been inconsistent.Our objectives were to determine the relationships between HIV infection, virologic suppression with antiretroviral therapy (ART), in vivo measures of conduit artery and microvascular endothelial function, and circulating biomarkers of pathways associated with CVD.We performed a cross-sectional analysis of three prospectively enrolled groups from a single center: 28 were HIV-infected and virologically-suppressed on a regimen of FTC/TDF/EFV (HIV+ART+), 44 were HIV-infected but not on ART (HIV+ART-), and 39 were HIV-uninfected healthy volunteers (HIV-) matched to the HIV+ART- group for age, sex, smoking status, and height. None had diabetes, uncontrolled hypertension, known CVD, or other pro-inflammatory condition. Flow mediated dilation (FMD), nitroglycerin-mediated dilation (NTGMD), reactive hyperemia velocity time integral (RHVTI), and FMD/RHVTI of the brachial artery were measured, as well as circulating biomarkers of systemic inflammation, metabolism, oxidative stress, and endothelial activation.No significant differences were found amongst the three groups in FMD (P = 0.46), NTGMD (P = 0.42), RHVTI (P = 0.17), and FMD/RHVTI (P = 0.22) in unadjusted comparisons. Adjusted ANOVA models which included brachial artery diameter, demographics, and conventional CVD risk factors did not appreciably change these findings. In pairwise comparisons, the HIV+ART- group had significantly higher soluble tumor necrosis factor receptor II, soluble CD163, ?-2 microglobulin, interferon-?- induced protein-10, tissue inhibitor of metalloproteinase-1, and vascular cell adhesion molecule-1 compared to the other two groups (all p<0.05). Correlates of endothelial function differed between study groups.Although untreated HIV infection was associated with elevated levels of several biomarkers of inflammation and endothelial activation, we were unable to demonstrate differences in measures of conduit artery and microvascular endothelial function in this study population.

Project description:BACKGROUND:Immune activation is a strong predictor of disease progression in HIV infection. Combinatorial plasma biomarker signatures that represent surrogate markers of immune activation in both viremic and aviremic HIV patients on combination antiretroviral therapy (cART) have not been defined. Here, we identify a plasma inflammatory biomarker signature that distinguishes between both viremic and aviremic HIV patients on cART and healthy controls and examine relationships of this signature to markers of disease progression. METHODS:Multiplex profiling and ELISA were used to detect 15 cytokines/chemokines, soluble IL-2R (sIL-2R), and soluble CD14 (sCD14) in plasma from 57 HIV patients with CD4 nadir <300 cells/µl and 29 healthy controls. Supervised and unsupervised analyses were used to identify biomarkers explaining variance between groups defined by HIV status or drug abuse. Relationships between biomarkers and disease markers were examined by Spearman correlation. RESULTS:The majority (91%) of HIV subjects were on cART, with 38% having undetectable viral loads (VL). Hierarchical clustering identified a biomarker cluster in plasma consisting of two interferon-stimulated gene products (CXCL9 and CXCL10), T cell activation marker (sIL-2R), and monocyte activation marker (sCD14) that distinguished both viremic and aviremic HIV patients on cART from controls (p<0.0001) and were top-ranked in variables important in projection plots. IL-12 and CCL4 were also elevated in viremic and aviremic patients compared to controls (p<0.05). IL-12 correlated with IFN?, IFN?, CXCL9, and sIL-2R (p<0.05). CXCL10 correlated positively with plasma VL and percentage of CD16+ monocytes, and inversely with CD4 count (p?=?0.001, <0.0001, and 0.04, respectively). CONCLUSION:A plasma inflammatory biomarker signature consisting of CXCL9, CXCL10, sIL-2R, and sCD14 may be useful as a surrogate marker to monitor immune activation in both viremic and aviremic HIV patients on cART during disease progression and therapeutic responses.

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Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy.

Publications

Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy.

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