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 感染者的生存率显着提高，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。即便如此，HIV 感染、长期药物滥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 15 年中，我们以非常低的失访率（每年 <3.5%），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 感染的影响，慢性可卡因使用和长期 ART 暴露导致亚临床 CAD。我们收集了研究参与者的问卷数据、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。可卡因滥用非常普遍，是 AA 地区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) 维持和扩大我们主要由 HIV 感染 AA 组成的队列（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) 纵向研究长期使用可卡因和长期接触 ART 对 HIV 感染的 AA 中亚临床/临床 CAD 的发生和进展的影响； (3) 进行两项试点研究，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。我们将探索表观遗传机制，包括组蛋白修饰和 DNA 甲基化，这些机制有助于 HIV 感染的 AA 中药物诱导的基因表达谱。拟议的具体目标是：（1）通过一年的资助，我们建议维持/建立现有队列，作为独立资助的研究和其他针对艾滋病相关和艾滋病毒相关非艾滋病疾病的合作研究的平台，例如心脑血管疾病、神经和精神状态以及其他结果，（2）由于一年的资金有限，我们将纵向研究（仅两次就诊：一次就诊和一次新就诊）ART 引起的亚临床和临床效果如何冠状动脉感染 HIV 的非裔美国人 (AA) 长期使用可卡因会加剧疾病，(3) 研究长期使用可卡因如何影响 HIV 相关神经认知功能障碍，(4) 研究与 HIV 相关神经认知功能障碍相关的表观遗传变化，(5) 研究与 HIV 相关的亚临床动脉粥样硬化相关的表观遗传变化。只有对这一特征极其明确的群体进行持续跟踪，才能实现这些目标。借助包括高级成像数据在内的纵向数据，拟议的研究将在旨在更好地了解 HIV 感染、可卡因使用和长期 ART 暴露患者的 CAD 并采取预防措施的研究中发挥至关重要的作用。