HIV infection and reverse cholesterol transport

HIV感染和逆转胆固醇转运

• 批准号: 6589812
• 负责人: MICHAEL Ilya BUKRINSKY
• 金额: $ 4.03万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589812
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; atherosclerosis; blood chemistry; blood lipid; cholesterol; coronary disorder; enzyme linked immunosorbent assay; high density lipoproteins; human tissue; lipid metabolism; lipid transport; lipodystrophy; macrophage; protease inhibitor

DESCRIPTION (provided by applicant): Dysregulation of lipid metabolism is a common feature of HIV infection. It is most often observed in patients treated with protease inhibitors, but has been also described as a side effect of other classes of anti-HIV drugs. Abnormalities in lipid metabolism put HIV-infected patients at high risk for developing atherosclerosis and heart disease. Therefore, studies of lipid regulation should accompany development of new anti-HIV compounds. Unfortunately, mechanisms responsible for atherogenic effect of anti-HIV drugs are not understood. Based on similarities in lipid abnormalities between AIDS patients and patients with type II diabetes, where defects of reverse cholesterol transport were found to play a major pathogenic role in lipid dysregulation, and on our preliminary results that show suppression of cholesterol efflux by HIV infection, we hypothesize that a similar mechanism applies to HIV-infected individuals. To test this hypothesis and to analyze the effect on reverse cholesterol transport of anti-HIV compounds under investigation in the project funded by the parent grant, we propose the following Specific Aims: Specific Aim 1. To investigate the effect of HIV infection and anti-HIV compounds on rates of individual steps of reverse cholesterol transport in vitro. Specific Aim 2. To investigate the effects of HIV-1 infection and treatment with protease inhibitors on the status of reverse cholesterol transport in HIV-infected patients. The proposed studies address important research questions highly relevant to the goals of the parental grant. The knowledge obtained from this research would allow to improve AIDS therapy by suggesting targets for therapeutic treatment of lipid dysregulation and providing means for choosing compounds that lack this serious side-effect. The proposed collaboration provides a unique opportunity to perform such studies. The Australian collaborator, Dr. D. Sviridov, is a recognized expert with impressive track record in cholesterol transport and atherosclerosis. This research will be done primarily in Australia as an extension of the NIH grant #R01 AI 40386.

描述（由申请人提供）：脂质代谢失调是 HIV 感染的一个常见特征。它最常见于接受蛋白酶抑制剂治疗的患者，但也被描述为其他类别的抗艾滋病毒药物的副作用。脂质代谢异常使艾滋病毒感染者面临动脉粥样硬化和心脏病的高风险。因此，脂质调节的研究应该伴随着新的抗艾滋病毒化合物的开发。不幸的是，抗艾滋病毒药物导致动脉粥样硬化的机制尚不清楚。基于艾滋病患者和 II 型糖尿病患者血脂异常的相似性（发现反向胆固醇转运缺陷在血脂失调中起主要致病作用），以及我们的初步结果显示 HIV 感染抑制胆固醇外流，我们假设类似的机制适用于艾滋病毒感染者。为了检验这一假设并分析在母基金资助的项目中正在研究的抗 HIV 化合物对反向胆固醇转运的影响，我们提出以下具体目标： 具体目标 1. 研究 HIV 感染和抗 HIV 化合物的作用。 HIV化合物对体外逆转胆固醇转运各个步骤的速率的影响。具体目标 2. 研究 HIV-1 感染和蛋白酶抑制剂治疗对 HIV 感染者胆固醇反向转运状态的影响。拟议的研究解决了与父母补助金目标高度相关的重要研究问题。从这项研究中获得的知识将有助于改善艾滋病治疗，提出脂质失调治疗的目标，并提供选择没有这种严重副作用的化合物的方法。拟议的合作为开展此类研究提供了独特的机会。澳大利亚合作者 D. Sviridov 博士是一位公认的专家，在胆固醇转运和动脉粥样硬化方面拥有令人印象深刻的记录。这项研究将主要在澳大利亚进行，作为 NIH 拨款 #R01 AI 40386 的延伸。