HIV Protease Inhibitors and Atherosclerosis

描述：（由申请人提供）我们假设HIV蛋白酶 抑制剂改变巨噬细胞B类清道夫受体依赖性摄取， 胆固醇流出，从而促进脂质负载的形成， 巨噬细胞和动脉粥样硬化病变。使用艾滋病毒的一个主要缺点是 蛋白酶抑制剂的另一个重要作用是它们促进血脂异常的发展， 是动脉粥样硬化发展的一个确定的危险因素。许多 有报道表明蛋白酶抑制剂治疗和 动脉粥样硬化;然而，这还没有明确证明， 大规模临床试验。血脂异常，主要是增加 甘油三酯，不太可能完全解释 动脉粥样硬化病变，因为动脉粥样硬化是一种 不受单一因素控制的多因素疾病。我们 初步数据表明，艾滋病毒蛋白酶抑制剂有直接影响， 巨噬细胞是动脉粥样硬化病变中的关键细胞介质 发展载脂巨噬细胞的产生是一个关键事件， 动脉粥样硬化形成，并被认为是由于，部分，不受管制的摄取， 修饰的脂蛋白这种异常的胆固醇积累受到以下因素的影响 B类清道夫受体SR-BI和CD 36的功能。两 受体存在于动脉粥样硬化损伤和巨噬细胞上。此外，本发明还提供了一种方法， 这两种受体都可以介导脂蛋白胆固醇的摄取和外排 细胞胆固醇。我们的初步数据表明，腹膜 从给予HIV蛋白酶的LDL受体缺失小鼠中分离的巨噬细胞 抑制剂安普那韦、茚地那韦或利托那韦含有更多的SR-BI和CD 36 年龄匹配的对照组。此外，所有三种蛋白酶抑制剂 增加THP-1细胞中SR-BI和CD 36水平，我们的巨噬细胞模型 系统蛋白酶抑制剂也增加了细胞胆固醇含量 在体内和体外模型系统中，这与我们的研究结果一致。 假说.重要的是，给予安普那韦、茚地那韦或利托那韦的小鼠 动脉粥样硬化病变明显多于对照组小鼠。我们将测试两个 具体目标。目的1：确定HIV蛋白酶抑制剂对HIV感染的影响。 SR-BI和CD 36依赖性胆固醇摄取和流出。目标2：确定 白细胞（即，巨噬细胞等）HIV蛋白酶抑制剂的特异性作用 对LDL受体缺失小鼠动脉粥样硬化病变形成的影响， 移植来自SR-BI x LDLR和CD 36 x LDLR无效小鼠的骨髓。

DESCRIPTION: (provided by applicant) We hypothesize that HIV protease inhibitors alter macrophage class B scavenger receptor-dependent uptake and efflux of cholesterol thereby promoting the formation of lipid-laden macrophages and atherosclerotic lesions. A major drawback to the use of HIV protease inhibitors is that they promote the development of dyslipidemia, which is an established risk factor for the development of atherosclerosis. Numerous reports have suggested a causal link between protease inhibitor therapy and atherosclerosis; however, this has not been unequivocally demonstrated in a large-scale clinical trial. The dyslipidemia, which is primarily an increase in triglycerides, is unlikely to completely account for the development of atherosclerotic lesions in HIV patients because atherosclerosis is a multifactorial disease that is not controlled by a single factor. Our preliminary data demonstrate that HIV protease inhibitors have direct effects on macrophages, which are critical cellular mediators in atherosclerotic lesion development. The generation of lipid-laden macrophages is a key event in atherogenesis and is thought to be due, in part, to unregulated uptake of modified lipoproteins. Such aberrant cholesterol accumulation is influenced by the functions of the class B scavenger receptors, SR-BI and CD36. Both receptors are found in atherosclerotic lesions and on macrophages. In addition, both receptors can mediate the uptake of lipoprotein cholesterol and the efflux of cellular cholesterol. Our preliminary data demonstrate that peritoneal macrophages isolated from LDL receptor null mice given the HIV protease inhibitors, amprenavir, indinavir, or ritonavir, contain more SR-BI and CD36 than aged-matched controls. In addition, all three protease inhibitors increased SR-BI and CD36 levels in THP-1 cells, our macrophage cell model system. The protease inhibitors also increased the cellular cholesterol content in both the in vivo and in vitro model systems, which is consistent with our hypothesis. Importantly, mice given amprenavir, indinavir, or ritonavir had significantly more atherosclerotic lesions than control mice. We will test two Specific Aims. Aim 1 : To determine the effects of HTV protease inhibitors on SR-BI and CD36 dependent cholesterol uptake and efflux. Aim 2: To determine the leukocyte (i.e., macrophages, etc.) specific effects of HIV protease inhibitors on atherosclerotic lesion formation in LDL receptor null mice that have been transplanted with bone marrow from SR-BI x LDLR and CD36 x LDLR null mice.