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

HIV、可卡因和长期使用 ART 对亚临床心血管疾病的影响

• 批准号: 8983355
• 负责人: SHENGHAN LAI
• 金额: $ 137.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8983355
• 关键词: Acquired Immunodeficiency Syndrome; Address; African American; Alcohol or Other Drugs use; Atherosclerosis; Baltimore; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cerebrovascular Disorders; Chronic; Clinical; Clinical Data; Cocaine; Cocaine Abuse; Coronary; Coronary Arteriosclerosis; Coronary Stenosis; DNA Methylation; Data; Development; Epigenetic Process; Funding; Gene Expression Profile; Genes; HIV; HIV Infections; Health; Heart Diseases; Image; Incidence; Individual; Investigation; Joints; Laboratories; Lead; Neurocognitive Deficit; Neurologic; Outcome; Participant; Pharmaceutical Preparations; Physical Examination; Pilot Projects; Play; Prevalence; Preventive measure; Questionnaires; Research; Research Design; Research Infrastructure; Research Personnel; Resources; Risk Factors; Role; Specimen; Time; United States National Institutes of Health; Visit; Work; antiretroviral therapy; cocaine use; cohort; follow-up; histone modification; improved; interest; neurotoxicity; premature

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.

由于HIV感染者的生存率显著提高，早发性冠状动脉疾病（CAD）已成为HIV感染者面临的最严重的临床挑战之一。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）暴露的综合影响从未得到彻底研究。在过去的15年中，失访率非常低（每年<3.5%），我们在巴尔的摩建立了一个由1,400名无心血管症状的非裔美国人（AA）组成的队列，以研究HIV感染、慢性可卡因使用和长期ART暴露对亚临床CAD的影响。我们收集了研究参与者的问卷调查数据、体格检查数据、生物标本、实验室数据、临床数据和心脏CT数据。可卡因滥用是非常普遍的，并作为一个强大的辅助因素艾滋病毒恶化的AA。可卡因滥用和HIV感染的表观遗传学改变决定了几个关键基因的表达。这个项目的目标是（1）维持和扩大我们的队列，主要是艾滋病毒感染的AA（一些HIV阴性作为对照）并巩固基础设施，为广泛的研究工作提供平台;（2）纵向检查慢性可卡因使用和长期ART暴露对HIV感染的AA中亚临床/临床CAD的发展和进展的影响;和（3）进行两项初步研究，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变化。我们将探讨表观遗传学机制，包括组蛋白修饰和DNA甲基化有助于药物诱导的基因表达谱在艾滋病毒感染的AA。建议的具体目的是：（1）在为期一年的拨款下，我们建议维持/建立现有的队列研究，作为独立资助研究和其他合作研究的平台，这些研究涉及艾滋病相关和艾滋病相关的非艾滋病情况，例如心血管/脑血管疾病、神经和精神状况，以及其他结果;（2）由于一年的拨款有限，我们将纵向研究（只有两次访问：之前的访问，和一次新的访问）ART诱导的亚临床和临床冠状动脉疾病是如何在非裔美国人（AA）中因长期使用可卡因而加剧的（3）研究慢性可卡因使用如何影响HIV相关神经认知损害;（4）研究HIV相关神经认知损害的表观遗传学变化;（5）研究HIV相关亚临床动脉粥样硬化的表观遗传学变化。这些目标只能通过对这一特征非常明确的队列进行持续随访来实现。通过纵向数据，包括先进的成像数据，拟议的研究将在旨在更好地理解和预防艾滋病毒感染，可卡因使用和长期ART暴露的CAD的研究中发挥关键作用。