HIV, Inflammation, and Endothelial Dysfunction

随着联合抗逆转录病毒疗法(CART)死亡率的降低，心血管疾病 成为艾滋病毒感染患者的主要死亡原因。因为几种抗逆转录病毒药物会导致胰岛素 耐药性和血脂异常，动脉粥样硬化性疾病的风险增加主要归因于 这些毒品。然而，正在出现的证据表明，未经治疗的艾滋病毒感染在很大程度上有助于 未来心血管事件的风险。炎症和内皮细胞功能障碍是血管内皮细胞死亡的关键因素 普通人群中的动脉粥样硬化。HIV感染患者的血管病变增加 单核细胞趋化蛋白-1(MCP-1)水平升高时白细胞与内皮细胞的黏附 血管细胞黏附分子-1(VCAM-1)。在CART-NA患者中，这些黏附分子的水平 是增加的，内皮功能障碍是常见的。CART只能部分降低这些分子的水平 仅能部分恢复内皮功能。我们新的初步数据表明，抗炎药 己酮可可碱(PTX)可显著改善血流介导的肱动脉扩张，这是一项体内测量方法 在HIV感染者中，通过抑制白细胞的募集和黏附，可以改善内皮功能。使用 细胞模型，我们发现HIV感染的T细胞上调内皮细胞MCP-1，而PTX抑制 内皮细胞产生单核细胞趋化蛋白-1。我们将直接针对RFA-HL-08-003的一个具体目标，即 “研究艾滋病毒本身对血管内皮细胞的直接影响，并确定任何缓解因素” 合作研究。在这一应用中，我们将解决与艾滋病毒相关的炎症的中心假设 诱导内皮细胞功能障碍，而己酮可可碱可以逆转这种功能障碍。我们的具体目标是：(1)确定 己酮可可碱对HIV感染者内皮功能的影响及体外分析 HIV和PTX调节内皮细胞激活和损伤的机制。我们将调查 PTX在治疗试验中改善HIV相关内皮功能障碍的应用。我们亦会研究 HIV诱导的内皮功能障碍的机制以及PTX通过我们的IN逆转这一过程的能力 体外模型。这项研究既及时又有意义，因为它将超越观察性临床 通过治疗试验和机制研究来确定新的病因 炎症与内皮功能的关系及病理机制。如果己酮可可碱是 在建议的研究中发现在改善内皮功能方面有效，那么这种廉价、安全和 广泛使用的药物可以在更大规模的试验中进行研究，以减少艾滋病毒感染患者的心血管终点。

With the reduction in mortality due to combination antiretroviral therapy (cART), cardiovascular disease has emerged as a leading cause of death in HIV-infected patients. Because several antiretrovirals cause insulin resistance and dyslipidemia, the increased risk for atherosclerotic disease has been attributed primarily to these drugs. However, evidence is emerging that suggest untreated HIV infection contributes significantly to the risk for future cardiovascular events. Inflammation and endothelial cell dysfunction are key promoters of atherosclerosis in the general population. Vascular lesions in HIV-infected patients demonstrate increased leukocyte adhesion to the endothelium with elevated levels of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1). In cART-na¿ve patients, levels of these adhesion molecules are increased and endothelial dysfunction is common. cART only partly reduces levels of these molecules and only partly restores endothelial function. Our novel preliminary data suggest that the anti-inflammatory drug pentoxifylline (PTX) may significantly improve flow-mediated dilation of the brachial artery, an in vivo measure of endothelial function, in HIV-infected subjects by inhibiting leukocyte recruitment and adhesion. Using a cellular model, we found that HIV-infected T cells upregulate endothelial MCP-1 and that PTX inhibits endothelial production of MCP-1. We will directly address a specific objective of RFA-HL-08-003, which is to "examine the direct effects of HIV itself on the endothelium and identify any mitigating factors" in the proposed collaborative studies. In this application, we will address the central hypothesis that HIV-related inflammation induces endothelial cell dysfunction that is reversed with pentoxifylline. Our Specific Aims are (1) To determine the effects of pentoxifylline on endothelial function in HIV-infected subjects and (2) To analyze in vitro mechanisms by which HIV and PTX modulate endothelial cell activation and injury. We will investigate the utility of PTX to improve HIV-related endothelial dysfunction in therapeutic trials. We will also study the mechanism of HIV-induced endothelial dysfunction and the ability of PTX to reverse this process using our in vitro models. This research is both timely and significant because it will move beyond observational clinical research by involving both therapeutic trials and mechanistic investigations to identify novel causal relationships and pathologic mechanisms between inflammation and endothelial function. If pentoxifylline is found to be effective in improving endothelial function in the proposed studies, then this inexpensive, safe, and widely available drug can be studied in larger trials to reduce cardiovascular endpoints in HIV-infected patients.