Inflammation, Viral Replication, and Atherosclerosis in Treated HIV Infection

描述(由申请人提供)： 最近的研究表明，艾滋病毒患者发生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。我们小组是第一批证明HIV感染与加速的动脉粥样硬化独立相关的小组之一，通过测量颈动脉内膜中层厚度(IMT)来衡量，并且HIV相关的炎症可能是加速动脉粥样硬化的驱动因素。在HAART期间，艾滋病毒疾病独立于任何药物特有的毒性增加心血管疾病风险的机制尚不清楚。我们假设，即使很好地控制了艾滋病毒感染，也与心血管风险独立相关，进一步减少与艾滋病毒相关的炎症，添加新的抗逆转录病毒药物也将降低心血管风险。我们将对300名接受治疗并被抑制的艾滋病毒感染患者和75名未感染对照(目标1)进行横断面研究，并对每50名艾滋病毒感染患者进行两项小型临床试验(目标2，3)，以研究艾滋病毒感染、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。我们提出以下具体目标：目标1：确定传统的和新型的炎症标志物对内皮功能和IMT进展的影响；目标2：确定在临床检测不到的艾滋病毒RNA水平的长期抗逆转录病毒治疗的受试者中，雷替格雷的“强化”是否会改善内皮功能，并确定这种效应是否通过炎症标志物、脂蛋白和/或血栓因子的变化来调节；以及目标3：确定CCR5抑制对炎症和内皮功能的潜在有益方面，以臂动脉反应性来衡量。这一应用结合了(1)从现有的艾滋病毒感染者队列中快速招募受试者的能力；(2)专门和成功的心脏病学研究成像实验室；(3)开创了感染中有利于动脉粥样硬化的脂蛋白研究的实验室；(4)NIAID的高级研究人员合作进行创新的免疫学分析。了解HIV感染中心血管疾病的发病机制将为预测、管理和治疗HIV和HAART相关并发症提供必要的信息，随着老龄化的发生，这是一个越来越重要的问题。(摘要结束)

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)