Inflammatory Mechanisms and Treatment Strategies for Atherosclerosis in HIV

HIV 患者动脉粥样硬化的炎症机制和治疗策略

• 批准号: 8314079
• 负责人: STEVEN K. GRINSPOON
• 金额: $ 101.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314079
• 关键词: ATP-Binding Cassette Transporters; Acute; Address; Adhesions; Aftercare; American Heart Association; Angiography; Aorta; Arterial Fatty Streak; Atherosclerosis; Attenuated; Biological Markers; CD14 gene; Cardiac; Cardiology; Cardiovascular Diseases; Cells; Central obesity; Cessation of life; Characteristics; Cholesterol; Chronic; Clinical; Communicable Diseases; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Death Rate; Development; Diabetes Mellitus; Disease; Down-Regulation; Dyslipidemias; Endocrinology; Endothelial Cells; Endothelium; Epidemiology; FCGR3B gene; Foam Cells; Functional disorder; Future; General Population; Grant; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Immune; Immune system; Impairment; Infection; Inflammation; Inflammatory; Interruption; Investigation; LDL Cholesterol Lipoproteins; Low-Density Lipoproteins; Lymphocyte Activation; Measures; Mediating; Metabolic; Morbidity - disease rate; Natural History; Patients; Pharmaceutical Preparations; Phase; Placebos; Play; Population; Positron-Emission Tomography; Prevention strategy; Production; Proteins; Randomized; Research Personnel; Risk Factors; Risk Marker; Role; Satellite Viruses; Science; Structure; System; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Vascular Endothelium; Viral; Viral Load result; Viremia; X-Ray Computed Tomography; abstracting; activator 1 protein; antiretroviral therapy; atherogenesis; atorvastatin; cardiovascular disorder risk; cohort; cytokine; fluorodeoxyglucose positron emission tomography; follow-up; immune activation; immune function; improved; indexing; longitudinal course; macrophage; migration; monocyte; mortality; nef Protein; novel; patient population; prevent; protein expression; randomized placebo controlled trial; response; symposium; translational approach; treatment strategy; vascular inflammation

DESCRIPTION (provided by applicant): Worldwide, survival in HIV-infected patients has remarkably improved with the use of highly active anti- retroviral therapy (HAART); however, survival in HIV-infected patients remains decreased compared to the general population in part due to excess deaths from non-infectious illnesses including cardiovascular disease(CVD). At the recent AHA State of the Science Conference on CVD in HIV Patients 2007, experts in cardiology, infectious diseases, endocrinology, and epidemiology agreed that CVD is an emerging problem for HIV patients and a significant need exists for studies to investigate mechanisms and potential therapies. Metabolic effects of ART increase traditionally recognized CV risk factors including dyslipidemia, diabetes mellitus, and central obesity, which are highly prevalent in the HIV population. Beyond these known increased CVD risk factors in HIV-infected patients, the HIV virus itself likely further promotes CVD through increased inflammation, immune activation, and viral factors. Atherosclerosis is an inflammatory disease in which monocytes and T lymphocytes play key roles in atheroma development. HIV infection causes alterations in the monocyte repertoire with expansion of the proinflammatory CD14+CD16+ monocyte subset and T lymphocyte activation. Furthermore, HIV viral factors are being recognized to possibly contribute to atherogenesis. HIV-1 Nef protein impairs efflux of cholesterol from macrophages by downregulation of ATP binding cassette transporter A1 (ABCA1), and thus, promotes foam cell formation. We hypothesize these immune alterations and viral factors promote atherosclerosis development in HIV patients. To further address these questions, we will investigate early measures of atherosclerosis in patients during acute HIV infection and follow these measures longitudinally over time during prolonged HIV infection, hypothesizing that proatherogenic changes will occur in the vascular endothelium during acute infection when viral burden is at its peak. In addition, to investigate potential mechanisms, we will utilize this longitudinal cohort of patients followed from the time of acute HIV infection to investigate the role of proinflammatory alterations of monocyte and T cells by HIV as well as ABCA1 impairment by HIV nef protein as potential key mechanisms we hypothesize to underlie the relationship between HIV infection and atherosclerosis. We further hypothesize that statin therapy will decrease plaque inflammation and have immunomodulatory effects on proinflammatory monocytes and T lymphocyte response in HIV patients. Elucidation of associated atherogenic indices in response to statins will help to guide future strategies of preventive and targeted therapy to decrease CVD in this population. The proposed grant will investigate the effects of the HIV virus and associated changes in the immune system on the development of atherosclerosis during acute HIV infection and after viral suppression with antiretroviral therapy. In addition, the potential beneficial effects of a cholesterol-lowering medication on vascular inflammation and immune cells will be investigated in HIV patients with early asymptomatic atherosclerosis. (End of Abstract)

描述（由申请人提供）： 在全球范围内，使用高度活跃的抗逆转录病毒疗法（HAART），HI​​V感染患者的生存已明显改善。然而，与普通人群相比，艾滋病毒感染患者的生存仍然下降，部分原因是包括心血管疾病（CVD）在内的非感染疾病过多的死亡。在2007年艾滋病毒患者CVD科学科学会议的最新AHA状态上，心脏病学，传染病，内分泌学和流行病学专家一致认为，CVD是HIV患者的新兴问题，并且对研究的重要需求是研究机制和潜在疗法的研究。艺术的代谢作用传统上识别出的CV风险因素，包括血脂异常，糖尿病和中央肥胖症，它们在HIV人群中非常普遍。除了这些已知的HIV感染患者中CVD危险因素增加之外，HIV病毒本身可能通过增加的炎症，免疫激活和病毒因素进一步促进CVD。动脉粥样硬化是一种炎症性疾病，单核细胞和T淋巴细胞在动脉瘤发育中起关键作用。 HIV感染引起单核细胞库的改变，促炎CD14+ CD16+单核细胞子集和T淋巴细胞激活的扩展。此外，正在认识到HIV病毒因子可能有助于动脉粥样硬化。 HIV-1 NEF蛋白通过下调ATP结合盒式转运蛋白A1（ABCA1），从而损害了胆固醇的外排，因此促进了泡沫细胞的形成。我们假设这些免疫改变，病毒因素促进了HIV患者的动脉粥样硬化发展。为了进一步解决这些问题，我们将调查急性HIV感染期间患者动脉粥样硬化的早期措施，并在长期HIV感染期间随着时间的流逝纵向遵循这些措施，假设在病毒负担达到急性负担时，急性感染期间血管内皮中会发生促性疗法变化。此外，为了研究潜在的机制，我们将利用从急性HIV感染开始的患者纵向队列来研究HIV对单核细胞和T细胞的促炎改变的作用，以及HIV NEF NEF NEF NEF NEF NEF蛋白作为潜在的关键机制，我们在HIV Inve Inveplie和A TheRoscler Invection和Athers a there a there sthersecters之间的潜在机制。我们进一步假设他汀类药物疗法将减少斑块炎症，并对HIV患者的促炎单核细胞和T淋巴细胞反应产生免疫调节作用。阐明相关的动脉粥样硬化指数对他汀类药物的响应将有助于指导未来的预防和靶向疗法策略，以减少该人群中的CVD。拟议的赠款将研究HIV病毒的影响以及免疫系统对急性HIV感染期间动脉粥样硬化发展以及通过抗逆转录病毒疗法的病毒抑制后的影响。此外，将研究降低胆固醇药物对血管炎症和免疫细胞的潜在有益作用，在早期无症状动脉粥样硬化患者中。 （抽象的结尾）