Exosomes from HIV-activated monocytes induce endothelial cell activation

 描述（由申请人提供）： 艾滋病毒感染者的心血管疾病仍然比其年龄预期的更广泛。虽然成功的治疗可以抑制病毒载量，但免疫重建并不完全 办妥了一批一些HIV感染者持续具有活化的1型干扰素（IFN）单核细胞特征，循环中脂多糖（LPS）水平较低。我们报道了HIV感染者的单核细胞增加了主要的脂质摄取和泡沫细胞形成的清道夫受体。我们还发现，HIV感染的单核细胞比对照未感染的受试者积累更多的脂质。我们假设，激活的单核细胞从艾滋病毒感染的个人是一个危险因素不同的艾滋病毒阴性的受试者动脉粥样硬化，并携带一个激活的表型，支持修改脂质摄取。在这里，我们表明，称为外泌体的脂质囊泡，从IFN/LPS引发的单核细胞分泌，可以转移到人内皮细胞，并诱导粘附分子ICAM-1和CCL 2（MCP-1）。单核细胞通常分泌外泌体，并且可以将miR、mRNA、细胞因子和蛋白质转移至其他细胞，包括内皮细胞。我们将从HIV感染者和对照个体中分离单核细胞外泌体，以确定它们在内皮细胞活化中的作用。我们提出 以确定外泌体中的哪些因子诱导内皮细胞促进单核细胞粘附和迁移，这是动脉粥样硬化斑块形成的最初步骤。从单核细胞外泌体中鉴定的因子可能为治疗提供新的靶点，可以降低心血管风险以及其他HIV相关的合并症。

 DESCRIPTION (provided by applicant): HIV-infected individuals continue to have more extensive cardiovascular disease than expected for their age. While successful therapy can suppress viral load, immune reconstitution is not fully achieved. Some individuals with HIV infection continue to have an activated type 1 interferon (IFN) monocyte profile with circulating low levels of lipopolysaccharide (LPS). We reported that monocytes from HIV-infected subjects have an increase in the major scavenger receptor for lipid uptake and foam cell formation. We also showed that monocytes from HIV infection accumulated more lipids than control uninfected subjects. We hypothesize that activated monocytes from HIV-infected individuals are a risk factor different from HIV-negative subjects with atherosclerosis and carry an activated phenotype that supports modified lipid uptake. Here we show that lipid vesicles called exosomes, secreted from IFN/LPS primed monocytes, can be transferred to human endothelial cells and induce the adhesion molecules ICAM-1 and CCL2 (MCP-1). Monocytes normally secrete exosomes and can transfer miRs, mRNA, cytokines and proteins to other cells including endothelial cells. We will isolate monocyte exosomes from HIV-infected and control individuals to determine their role in endothelial cell activation. We propose to identify what factors in the exosomes induce endothelial cells to promote monocyte adhesion and migration, the initial steps for atherosclerotic plaque formation. Factors identified from monocyte exosomes may present novel targets for treatment that could decrease cardiovascular risk as well as other HIV-associated co-morbidities.