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

由于艾滋病毒感染者的生存率显著提高，过早冠状动脉疾病（CAD）已成为艾滋病毒感染者面临的最严重的临床挑战之一。即便如此，艾滋病毒感染、慢性药物使用和长期抗逆转录病毒治疗（ART）的综合影响从未得到彻底调查。在过去的15年中，由于失踪率非常低（每年<3.5%），我们在巴尔的摩建立了一个由1400名心血管无症状非洲裔美国人（AAs）组成的队列，以调查HIV感染、慢性可卡因使用和长期抗逆转录病毒治疗对亚临床CAD的影响。我们收集了研究参与者的问卷调查资料、体格检查资料、生物标本、实验室资料、临床资料和心脏CT资料。可卡因滥用非常普遍，是艾滋病病毒在艾滋病地区恶化的一个有力的辅助因素。可卡因滥用和HIV感染的表观遗传改变决定了几个关键基因的表达。该项目的目标是：(1)维持和扩大主要感染爱滋病病毒的爱滋病患者（部分爱滋病病毒阴性作为对照），巩固基础设施，为广泛的研究工作提供平台；(2)纵向研究慢性可卡因使用和长期ART暴露对hiv感染AAs亚临床/临床CAD的发展和进展的影响；(3)开展两项初步研究，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变化。我们将探讨包括组蛋白修饰和DNA甲基化在内的表观遗传机制对hiv感染AAs药物诱导基因表达谱的影响。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，作为艾滋病相关和艾滋病毒相关的非艾滋病疾病（如心/脑血管疾病、神经和精神状态以及其他结果）的独立资助研究和其他合作研究的平台；(2)由于一年的资金有限，我们将进行纵向研究（仅两次访问）；(3)研究慢性可卡因使用如何影响HIV相关神经认知功能障碍，(4)研究HIV相关神经认知功能障碍的表观遗传变化，(5)研究HIV相关亚临床动脉粥样硬化的表观遗传变化。这些目标只能通过对这一极具特征的队列的持续随访来实现。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、可卡因使用和长期抗逆转录病毒治疗者的CAD和预防措施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.