Effects of HIV, Cocaine, and Prolonged ART Use on Subclinical Cardiovascular Disease

由于HIV感染者存活率的显著提高，早发冠状动脉疾病(CAD)已成为HIV感染者面临的最严重的临床挑战之一。尽管如此，艾滋病毒感染、慢性药物使用和长期接触抗逆转录病毒疗法(ART)的综合影响从未得到彻底调查。在过去的15年里，以非常低的随访率(每年3.5%)，我们在巴尔的摩建立了1400名心血管无症状非裔美国人(AA)的队列，以调查HIV感染、长期使用可卡因和长期暴露于ART对亚临床CAD的影响。我们收集了研究参与者的问卷数据、体检数据、生物标本、实验室数据、临床数据和心脏CT数据。可卡因滥用非常普遍，是AAS中艾滋病毒恶化的一个强有力的辅助因素。可卡因滥用和艾滋病毒感染的表观遗传变化决定了几个关键基因的表达。这个项目的目标是(1)维持和扩大我们主要感染艾滋病毒的AA(一些艾滋病毒阴性的AA作为对照)的队列，并巩固基础设施，为广泛的研究工作提供平台；(2)纵向研究长期使用可卡因和长期暴露于ART对艾滋病毒感染的AA中亚临床/临床冠心病的发展和进展的影响；以及(3)进行两项先导性研究，以调查与HIV相关的神经认知障碍和亚临床冠状动脉粥样硬化相关的表观遗传学变化。我们将探索包括组蛋白修饰和DNA甲基化在内的表观遗传学机制在HIV感染的AAs中促进药物诱导的基因表达谱。建议的具体目标是：(1)在一年的资助下，我们建议维持/建立现有的队列，作为独立资助的研究和其他合作研究的平台，这些研究涉及与艾滋病相关的和与艾滋病毒相关的非艾滋病疾病，如心脑血管疾病、神经和精神状况，以及其他结果；(2)由于一年的资金有限，我们将纵向研究(只有两次访问：以前的访问和新的访问)在感染艾滋病毒的非洲裔美国人(AAs)中，长期使用可卡因如何加剧ART引起的亚临床和临床冠状动脉疾病，(3)研究长期使用可卡因对HIV相关神经认知损害的影响；(4)研究HIV相关神经认知损害的表观遗传学改变；(5)研究HIV相关亚临床动脉粥样硬化的表观遗传学改变。这些目标只有在这一极具特点的群体继续采取后续行动的情况下才能实现。有了纵向数据，包括先进的成像数据，这项拟议的研究将在旨在更好地了解艾滋病毒感染、使用可卡因和长期暴露于ART的人的冠心病的研究中发挥关键作用。

Because of the dramatic improvement in survival among people with HIV infection, premature coronary artery disease (CAD) has become one of the most serious clinical challenges facing HIV-infected individuals. Even so, the combined effects of HIV infection, chronic substance use, and prolonged antiretroviral therapy (ART) exposure have never been thoroughly investigated. In the past 15 years, with a very low lost-to-follow-up rate (<3.5% per year), we have built a cohort of 1,400 cardiovascularly asymptomatic African Americans (AAs) in Baltimore to investigate the effects of HIV infection, chronic cocaine use, and prolonged ART exposure on subclinical CAD. We have collected questionnaire data, physical examination data, biologic specimens, laboratory data, clinical data, and cardiac CT data from the study participants. Cocaine abuse is highly prevalent and serves as a powerful co-factor for HIV exacerbation in AAs. Epigenetic alterations in cocaine abuse and HIV infection determine expression of several critical genes. The objectives of this project are to (1) maintain and expand our cohort of mainly AAs with HIV infection (some HIV negative as controls) and consolidate infrastructure to provide a platform for a wide range of research efforts; (2) examine longitudinally the effects of chronic cocaine use, and prolonged ART exposure on the development and progression of subclinical/clinical CAD in HIV-infected AAs; and (3) conduct two pilot studies to investigate epigenetic changes in relation to HIV-associated neurocognitive impairment and subclinical coronary atherosclerosis. We will explore the epigenetic mechanisms including histone modification and DNA methylation contribute to drug-induced gene expression profile in HIV-infected AAs. The proposed specific aims are:(1) with a one-year funding, we propose to maintain/build the existing cohort as a platform for independently funded studies and other collaborative research on AIDS-related and HIV-associated non-AIDS conditions such as cardiovascular/cerebrovascular disease, neurologic and psychiatric status, and other outcomes, (2) due to limited funding for one year, we will examine longitudinally (only two visits: a previous visit, and a new visit) how ART-induced subclinical and clinical coronary artery disease is exacerbated by chronic cocaine use in African Americans (AAs) with HIV infection, (3) to investigate how HIV-associated neurocognitive impairment is impacted by chronic cocaine use, (4) to investigate epigenetic changes in relation to HIV-associated neurocognitive impairment, and (5) to investigate epigenetic changes in relation to HIV-associated subclinical atherosclerosis. These aims can be addressed only with continued follow-up of this extremely well-characterized cohort. With longitudinal data, including advanced imaging data, the proposed study will play a crucial role in studies designed to lead to better understanding and preventive measures for CAD in those with HIV infection, cocaine use, and prolonged ART exposure.