HIV Disease and Impairement of High Density Lipoprotein Metabolism

描述(由申请人提供)：心血管疾病(CVD)对艾滋病毒感染者的总体发病率有很大贡献。从流行病学和前瞻性来看，最能预测动脉粥样硬化的因素是血脂异常和细胞内胆固醇代谢受损。HIV感染患者的血脂异常主要归因于抗逆转录病毒药物，特别是蛋白酶抑制剂，但导致血脂异常的具体机制尚未完全确定。对艾滋病毒感染本身引起的脂类代谢变化更是知之甚少。在这项应用中，我们提出了一项针对HIV感染患者的前瞻性研究，以表征与HIV-1感染和抗逆转录病毒药物相关的血液中关键的抗动脉粥样硬化脂蛋白-高密度脂蛋白(高密度脂蛋白)的代谢和功能变化。我们还将把这些变化与这些患者动脉粥样硬化进展的替代指标相关联。体外研究将探讨HIV介导的对高密度脂蛋白的影响机制，具体目标如下：具体目标1：研究LHIV疾病对动脉粥样硬化和代谢紊乱的影响。。具体目的2：研究HIV疾病对高密度脂蛋白组成和结构的影响。具体目标3：描述HIV疾病对高密度脂蛋白功能的影响。具体目标4：描述导致高密度脂蛋白代谢障碍的细胞机制。。这项建议中描述的研究是一个多PI计划，将依赖于三个地点的临床心脏病专家、基础科学心血管研究人员和病毒学家的合作努力：乔治华盛顿大学、哈佛大学和BakerlDI心脏和糖尿病研究所。 公共卫生相关性：这项拟议的研究与公共卫生高度相关，因为它调查了艾滋病毒感染者动脉粥样硬化风险高的原因。鉴于10%-30%的艾滋病毒感染者存在某种形式的心血管疾病的证据，而动脉粥样硬化是心血管疾病的主要潜在原因，动脉粥样硬化成为艾滋病毒疾病的主要并发症之一。然而，HIV感染和抗HIV治疗与动脉粥样硬化的发展之间的联系机制还不完全清楚，这使得拟议的研究对基础科学和临床研究都具有非常重要的意义。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) contributes substantially to the overall morbidity of HIV-infected individuals. Factors that epidemiologically and prospectively are the strongest predictors of .atherosclerosis are dyslipidemia and impairmen of intracellular cholesterol metabolism. Dyslipidemia in HIV-infected patients has been attributed mainly to antiretroviral drugs, in particular protease inhibitors, but specific mechanisms responsible for dyslipidemia have not been fully characterized. Even less is known about changes in lipid metabolism induced by HIV infection itself. In this application we propose a prospective study with HIV-infected patients to characterize changes in metabolism and functionality of High Density Lipoprotein (HDL), the key anti-atherogenic lipoprotein in the blood, associated with HIV-1 infection and anti-retroviral drugs. We will also correlate these changes with the surrogate measures of progression of atherosclerosis in these patients. Studies in vitro will address the mechanism of HIV-mediated effect on HDL The following Specific Aims are proposed: . Specific Aim 1: To characterize effects oLHIV disease on atherosclerosis and metabolic dysregulation. . Specific Aim 2: To characterize the effect of HIV disease on HDL composition and structure. Specific Aim 3: To characterize effects of HIV disease on HDL functionality. Specific Aim 4: To characterize cellular mechanisms responsible for impairment of HDL metabolism. . Research described in this proposal is a mUlti-PI program that will rely on collaborative efforts of clinical cardiologists, basic science cardiovascular researchers and virologists at three sites: the George Washington University, Harvard University and BakerlDI Heart and Diabetes Research Institute. PUBLIC HEALTH RELEVANCE: The proposed research is highly relevant to Public Health as it investigates the reason for high risk of atherosclerosis in HIV-infected subjects. Given that 10-30% of HIV-infected individuals present evidence of some form of cardiovascular disease, and atherosclerosis is the main underlying cause of cardiovascular disease, atherosclerosis becomes one of the main complications of HIV disease. However, mechanisms connecting HIV infection and anti-HIV treatment with development of atherosclerosis are not fully understood, making proposed study highly significant both for basic science and clinical research.