Lipogenesis & Lipoprotein Complications of HIV Therapy

脂肪生成

• 批准号: 7167112
• 负责人: David Yiu-Kwan Hui
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-19 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167112
• 关键词: AIDS therapy; HAART (highly active antiretroviral therapy); HIV infections; apolipoproteins; blood lipoprotein metabolism; cardiovascular disorder risk; clinical research; drug adverse effect; drug screening /evaluation; efavirenz; helper T lymphocyte; high density lipoproteins; host organism interaction; human immunodeficiency virus 1; human subject; human therapy evaluation; hyperlipidemia; laboratory mouse; lipid biosynthesis; lopinavir; nevirapine; protease inhibitor; reverse transcriptase inhibitors; ritonavir; virus infection mechanism

DESCRIPTION (provided by applicant): It is well recognized that HIV infection significantly decreases total- and HDL-cholesterol levels in plasma. The initiation of protease inhibitor (Pl)-based highly active anti retro viral therapy (HAART) generally leads to dyslipidemia with total plasma cholesterol and triglyceride levels far exceeding the normal range. However, HDL-cholesterol level remains low in a majority of Pi-treated patients. In contrast, treatment that includes non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine and efavirenz increases HDL-cholesterol. However, whether NNRTI-induced increase in HDL-cholesterol represents a unique property of these drugs or is simply a manifestation of a return to health remains unknown. The latter possibility would indicate that PI therapy, which does not normalize plasma HDL-cholesterol, directly reduces HDL levels in HIV infected subjects even with its reduction of viral load and health improvement. These two possibilities need to be distinguished to design the most effective treatment option to reduce the metabolic abnormalities of HAART. Another unanswered question is whether the NNRTI-induced increase in HDL is atheroprotective or whether the HDL increase is due to accumulation of dysfunctional HDL that contributes to atherosclerosis. The goals of this project are: (1) to delineate the mechanism by which HIV infection reduces HDL levels, (2) identify the pathway(s) by which restoration of health with PI versus NNRTI results in diverging effects on HDL levels, and (3) to ascertain the atheroprotective versus pro-atherogenic potentials of the HDL in patients receiving NNRTI. Specific Aim 1 will compare the fractional synthetic rates of the HDL major apolipoprotein apoA-l and the cholesterol efflux potential of macrophages and HDL/apoAl in seronegative subjects with treatment- naive HIV-infected individuals with CD4+ cell counts of >350 or <200 cells mu L to determine the impact of HIV infection and immune functions on HDL biosynthesis and metabolism. Enzymes responsible for lipidation, maturation, and remodeling of HDL will also compared to determine if differences are due to changes in expression and/or activity of these proteins. Aim 2 will compare the same HDL metabolic parameters in the HIV infected subjects after initiation of (i) atazanavir, (ii) lopinavir/ritonavir, or (iii) efavirenz therapy to identify the difference between health restoration and treatment-specific effects on HDL metabolism. Aim 3 will compare the functionality of the HDL after HAART therapy to determine if these are pro- or anti-atherogenic.

描述（由申请人提供）：众所周知，HIV感染可显着降低血浆中的总和HDL-胆固醇水平。基于蛋白酶抑制剂（PL）的高度活性抗复古病毒疗法（HAART）的启动通常会导致血脂异常，总血浆胆固醇和甘油三酸酯水平远远超过正常范围。但是，大多数PI治疗患者中HDL-胆固醇水平仍然很低。相反，包括非核苷逆转录酶抑制剂（NNRTI）奈韦拉平和efavirenz的治疗增加了HDL-胆固醇。但是，NNRTI诱导的HDL-胆固醇是否代表了这些药物的独特特性，还是仅仅是恢复健康的体现。后一种可能性表明，不正常血浆HDL-胆固醇的PI疗法直接降低了HIV感染受试者的HDL水平，即使病毒载量减少并改善了健康状况。需要区分这两种可能性，以设计最有效的治疗选择，以减少HAART代谢异常。另一个未解决的问题是，NNRTI诱导的HDL的增加是动脉保护性的，还是HDL的增加是否是由于功能障碍HDL的积累，导致动脉粥样硬化。 The goals of this project are: (1) to delineate the mechanism by which HIV infection reduces HDL levels, (2) identify the pathway(s) by which restoration of health with PI versus NNRTI results in diverging effects on HDL levels, and (3) to ascertain the atheroprotective versus pro-atherogenic potentials of the HDL in patients receiving NNRTI.具体目标1将比较HDL主要的载脂蛋白apoA-L的分数合成速率以及巨噬细胞和HDL/apoal在血清诺和HDL/apoal中的胆固醇外排潜能，并具有治疗的HIV感染的HIV感染的HIV感染的个体，具有CD4+细胞计数的CD4+细胞计数> 350或<200细胞Mu l> 350或<200型细胞功能，并确定HIN的影响。代谢。负责HDL脂化，成熟和重塑的酶也将比较确定差异是否是由于这些蛋白质的表达和/或活性的变化所致。 AIM 2将比较（i）atazanavir，（ii）lopinavir/ritonavir，或（iii）efavirenz疗法，比较艾滋病毒感染受试者中相同的HDL代谢参数，以鉴定健康恢复与治疗特异性对HDL代谢的影响之间的差异。 AIM 3将比较HAART治疗后HDL的功能，以确定这些功能是促或抗动脉粥样硬化的。