The impact of HIV driven T cell immune activation in angiogenic CD8 T cell function: the role of PAR1 signaling

摘要 与普通人群相比，艾滋病毒感染患者患心血管疾病的风险是普通人的两倍。这个 HIV感染患者心血管事件的主要驱动因素与慢性免疫有关 激活、全身性炎症和内皮功能障碍。连接HIV驱动的分子通路 慢性T免疫激活、血管炎症和心血管疾病风险增加在很大程度上 未知。在这项提案中，我们将调查驱动血管的潜在机制 通过关注血管生成的CD8 T细胞(CD8Tangs)的功能，在HIV感染过程中的炎症/损害。 在生理条件下，唐细胞通过促进分化和促进血管内皮细胞修复发挥作用。 血管损伤处内皮祖细胞的增殖。CD8唐细胞的作用机制 子集的区分和功能没有很好的定义。我们假设艾滋病毒感染会导致免疫 CD8唐细胞活化并损害其促进血管修复的能力及慢性干预 这一途径导致血管炎症和/或风险。在这个提案中，我们将：1)识别分子 CD8唐细胞分化和功能的途径及PAR1信号在其中的作用 路径。2)确定HIV驱动的T细胞免疫激活对CD8唐细胞分化和/或 并评估其与HIV感染患者心血管风险/疾病的关系。3) 从机制上讲，在LCMV感染的小鼠模型中，我们将评估角色记忆(组织驻留和 循环)CD8 T细胞经历CD8唐细胞分化并确定PAR1缺乏对 血管修复和心血管疾病进展。这些研究将建立CD8的机制 汤剂辨证论治与艾滋病病毒感染的关系。此外，这些研究还将识别新的分子 以恢复患者CD8唐功能为目标。本研究将在多个领域具有广泛的应用前景。 全身性炎症与心血管风险相关的炎症性疾病。 。

SUMMARY HIV infected patients have twice the risk of cardiovascular disease relative to the general population. The main drivers of cardiovascular events in patients with HIV infection are associated with chronic immune activation, systemic inflammation and endothelial dysfunction. The molecular pathways linking HIV-driven chronic T immune activation, vascular inflammation and increased risk of cardiovascular disease are largely unknown. In this proposal, we will investigate the underlying mechanisms driving vascular inflammation/damage during HIV infection by focusing in the function of angiogenic CD8 T cells (CD8 Tangs). Under physiological conditions, Tang cells play a role in endothelial repair by promoting differentiation and proliferation of endothelial progenitors at the site of vascular injury. The mechanisms involved in CD8 Tang cell subset differentiation and function are not well defined. We hypothesize that HIV infection drives immune activation of CD8 Tang cells and impairs their ability to promote vascular repair and, the chronic interference of this pathway contributes to vascular inflammation and/or risk. In this proposal we will: 1) Identify the molecular pathways involved in the differentiation and function of CD8 Tang cells and the role of PAR1 signaling in this pathway. 2) Identify the impact of HIV driven T cell immune activation in CD8 Tang cell differentiation and/or function and evaluate its relationship with cardiovascular risk/disease in patients with HIV infection. 3) Mechanistically, in a murine model of LCMV infection, we will evaluate the role memory (tissue resident and circulating) CD8 T cells to undergo CD8 Tang cell differentiation and determine the impact of PAR1 deficiency in vascular repair and cardiovascular disease progression. These studies will establish the mechanisms of CD8 Tang differentiation and function in health and HIV infection. In addition, these studies will identify new molecular targets to restore CD8 Tang function in patients. This research will have wide application in multiple inflammatory diseases in which systemic inflammation is associated with cardiovascular risk. .