Inflammation, Viral Replication, and Atherosclerosis in Treated HIV Infection

项目摘要/摘要 最近的研究表明，艾滋病毒患者发生心血管事件的风险增加； 然而，这种风险增加背后的机制仍不清楚。我们的团队是 第一个证明艾滋病毒感染与加速的 动脉粥样硬化，通过颈动脉-内膜中层厚度(IMT)来衡量，而HIV- 相关的炎症可能是加速动脉粥样硬化的原因。这个机制是通过 哪种HIV疾病不依赖于任何药物的特定毒性会增加心血管疾病的风险 HAART期间的疾病尚不清楚。我们假设，即使很好地控制了艾滋病毒感染， 与心血管风险独立相关，并进一步减少与艾滋病毒相关的 炎症加上新的抗逆转录病毒药物也会降低心血管风险。 我们将对300名接受治疗和抑制的艾滋病毒感染者进行横断面研究 患者和75名未感染的对照组(AIM 1)和两项关于50名艾滋病毒感染患者的小型临床试验 每个患者(目标2，3)研究艾滋病毒感染，炎症， 血栓形成、致动脉粥样硬化的脂蛋白和动脉粥样硬化的测量。我们建议 以下具体目标：目标1：确定传统标记和新标记的影响 炎症对内皮功能和IMT进展的影响；目标2：确定 临床长期抗逆转录病毒治疗受试者中雷替格雷韦的“强化”作用 检测不到的HIV RNA水平将改善内皮功能，并确定这种影响是否 由炎症标志物、脂蛋白和/或血栓因子的变化所介导；和目的 3：确定CCR5抑制炎症和 血管内皮细胞功能由臂动脉反应性来衡量。 此应用程序结合了(1)从现有队列中快速招募受试者的能力 (2)专门的和成功的心脏病学研究成像实验室， (3)率先研究前动脉粥样硬化性脂蛋白在感染中的实验室，以及(4) 来自NIAID的高级研究人员合作进行创新的免疫学分析。

PROJECT SUMMARY/ABSTRACT Recent studies suggest that HIV patients are at increased risk for cardiovascular events; however, the mechanisms underlying this increased risk remain unclear. Our group was one of the first to demonstrate that HIV infection is independently associated with accelerated atherosclerosis, as measured by carotid artery-intima media thickness (IMT), and that HIV- associated inflammation may be driving this accelerated atherosclerosis. The mechanism by which HIV disease independent of any drug-specific toxicity increases the risk of cardiovascular disease during HAART is not known. We hypothesize that even well controlled HIV infection is independently associated with cardiovascular risk and that further decreasing HIV-associated inflammation adding newer antiretroviral agents will also decrease cardiovascular risk. We will perform a cross-sectional study of 300 treated and suppressed HIV-infected patients and 75 uninfected controls (Aim 1) and two small clinical trials of 50 HIV-infected patients each (Aims 2,3) to study the relationship between HIV infection, inflammation, thrombosis, atherogenic lipoproteins, and measures of atherosclerosis. We propose the following specific aims: Aim 1: To determine the influence of traditional and novel markers of inflammation on endothelial function and IMT progression; Aim 2: To determine if "intensification" with raltegravir in subjects on long-term antiretroviral therapy with clinically undetectable HIV RNA levels will improve endothelial function, and to determine if this effect is mediated by alterations in inflammatory markers, lipoproteins and/or thrombotic factors; and Aim 3: To determine the potentially beneficial aspects of CCR5 inhibition on inflammation and endothelial function as measured by brachial artery reactivity. This application combines (1) the ability to rapidly recruit subjects from existing cohorts of HIV-infected subjects; (2) a dedicated and successful cardiology research imaging laboratory, (3) a laboratory that pioneered study of pro-atherosclerotic lipoprotein in infection, and (4) the collaboration of senior investigators from NIAID performing innovative immunology assays.