Inflammation, Viral Replication, and Atherosclerosis in Treated HIV Infection

描述（由申请人提供）： 最近的研究表明，艾滋病毒患者心血管事件的风险增加;然而，这种风险增加的机制仍不清楚。我们的研究小组是最早证明HIV感染与加速动脉粥样硬化（通过颈动脉内膜中层厚度（IMT）测量）独立相关的研究小组之一，并且HIV相关的炎症可能是加速动脉粥样硬化的驱动因素。HIV疾病独立于任何药物特异性毒性增加HAART期间心血管疾病风险的机制尚不清楚。我们假设，即使控制良好的HIV感染与心血管风险独立相关，进一步减少HIV相关炎症，增加新的抗逆转录病毒药物也会降低心血管风险。我们将对300名治疗和抑制的HIV感染患者和75名未感染的对照者进行横断面研究（目标1），并对各50名HIV感染患者进行两项小型临床试验（目标2，3），以研究HIV感染、炎症、血栓形成、致动脉粥样硬化脂蛋白和动脉粥样硬化指标之间的关系。我们提出了以下具体目标：目标1：确定传统和新型炎症标志物对内皮功能和IMT进展的影响;目标2：为了确定在接受长期抗逆转录病毒治疗且临床上检测不到HIV RNA水平的受试者中使用雷特格韦“强化”是否会改善内皮功能，并确定这种作用是否由炎症标志物的改变介导，脂蛋白和/或血栓形成因子;和目标3：确定CCR 5抑制炎症和内皮功能的潜在有益方面（通过肱动脉反应性测量）。该应用程序结合了（1）从现有的HIV感染受试者队列中快速招募受试者的能力;（2）一个专门且成功的心脏病学研究成像实验室，（3）一个率先研究感染中促动脉粥样硬化脂蛋白的实验室，以及（4）NIAID高级研究人员的合作，进行创新的免疫学检测。了解HIV感染中的心血管疾病发病机制将为HIV和HAART相关并发症的预测、管理和治疗提供必要的信息，这是随着衰老发生的一个越来越重要的问题。(End摘要）

DESCRIPTION (provided by applicant): 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. Understanding cardiovascular disease pathogenesis in HIV infection will provide essential information for the prediction, management, and therapy of HIV and HAART- associated complications, an increasingly important issue as aging occurs. (End of Abstract)