HIV PROTEASE INHIBITOR & LIPOPROTEIN RECEPTOR IMPAIRMENT

这个名为“蛋白酶抑制剂、致动脉粥样硬化脂蛋白和早期动脉粥样硬化”的合作项目包括三个提案。综上所述，这些研究将调查蛋白酶抑制剂的潜在动脉粥样硬化作用，并评估它们与亚临床心血管疾病的关系。HIV感染和相关的抗逆转录病毒治疗对血浆脂蛋白亚类和促氧化应激的影响将在不同的临床条件下进行评估，以确定HIV及其治疗，特别是蛋白酶抑制剂，是否会诱导致动脉粥样硬化环境。蛋白酶抑制剂可能促进人类动脉粥样硬化的机制将在一系列临床研究中进行探索：利用含和不含蛋白酶抑制剂的抗逆转录病毒治疗方案，治疗未感染的志愿者，以及使用沙利度胺减少晚期HIV感染患者TNFalpha的影响。体外细胞培养实验和动物模型将用于验证HIV蛋白酶抑制剂干扰某些低密度脂蛋白受体家族成员的正常功能，并且受体功能失调具有有害影响并可能加速动脉粥样硬化的假设。亚临床心血管疾病的存在及其与动脉粥样硬化脂蛋白表型和促氧化应激水平的关系将通过几种动脉粥样硬化标志物进行评估，包括血流介导的肱反应性、颈动脉内膜-中膜厚度、冠状动脉钙化和电子束计算机断层血管造影。还将检查吉非罗齐干预的影响。这三个项目是交织在一起的，都是通过一个伞式假设和共享的实验材料。为每个临床项目招募的受试者将提供用于其他项目的测定或分析的样品或测量方法。体外研究和动物模型的结果将影响临床研究的设计。共享资源包括管理/统计支持小组，核磁共振光谱脂质实验室和促氧化应激实验室。研究人员将对研究程序和结果进行持续的讨论，以确保研究小组之间的顺利互动，并激发新的分析和倡议。

This collaborative project, "Protease Inhibitors, Atherogenic Lipoproteins and Premature Atherosclerosis" comprises three proposals. Taken together, the studies will investigate potential atherosclerotic effects of protease inhibitors and assess their relationship to subclinical cardiovascular disease. The effects of HIV infection and associated antiretroviral therapy on plasma lipoprotein subclasses and pro-oxidant stress will be assessed under diverse clinical conditions to determine if HIV and its therapy, in particular protease inhibitors, induce a proatherogenic milieu. Mechanisms whereby protease inhibitors may promote atherosclerosis in humans will be explored in a series of clinical studies: utilizing antiretroviral regimens with and without protease inhibitors, treating uninfected volunteers and using thalidomide to reduce the effects of TNFalpha in patients with advanced HIV infection. In vitro cell culture experiments and animal models will be used to test the hypothesis that HIV protease inhibitors interfere with normal function of certain low density lipoprotein receptor family members, and that dysregulation of receptor function has a deleterious effect and may accelerate atherosclerosis. The presence of subclinical cardiovascular disease, and its relationship to the atherogenic lipoprotein phenotype and pro- oxidant stress levels will be assessed using several markers of atherosclerosis including flow-mediated brachial reactivity, carotid intima-media thickness, coronary calcification and electron beam computed tomographic angiography. The impact of intervention with gemfibrozil will also be examined. The three projects are interwoven, both through an umbrella hypothesis and shared experimental materials. Subjects recruited for each clinical project will provide samples or measures to be used in other projects' assays or analyses. Results from in vitro studies and the animal model will affect design of clinical studies. Shared resources include an administrative/statistical support group, NMR spectroscopic lipid laboratory and pro-oxidant stress laboratory. The investigators will conduct ongoing discussions of study procedures and results, both to ensure smooth interaction of the research groups and to stimulate new analyses and initiatives.