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: 7594984
• 负责人: STEVEN K. GRINSPOON
• 金额: $ 80.58万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7594984
• 关键词: ATP-Binding Cassette Transporters; Acute; Address; Adhesions; Aftercare; American Heart Association; Angiography; Aorta; Arterial Fatty Streak; Arts; Atherosclerosis; Attenuated; Biological Markers; 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; 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; follow-up; 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）： 在世界范围内，通过使用高效抗逆转录病毒疗法（HAART），艾滋病毒感染者的生存率显着提高；然而，与普通人群相比，艾滋病毒感染者的生存率仍然较低，部分原因是心血管疾病（CVD）等非传染性疾病导致的死亡人数过多。在最近举行的 AHA 2007 年 HIV 患者 CVD 科学会议上，心脏病学、传染病学、内分泌学和流行病学专家一致认为，CVD 是 HIV 患者的一个新问题，迫切需要进行研究来调查其机制和潜在的治疗方法。 ART 的代谢作用会增加传统上公认的心血管危险因素，包括血脂异常、糖尿病和中心性肥胖，这些因素在艾滋病毒人群中非常普遍。除了这些已知的 HIV 感染者 CVD 风险增加因素之外，HIV 病毒本身可能通过增加炎症、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，其中单核细胞和 T 淋巴细胞在动脉粥样硬化形成中发挥关键作用。 HIV 感染导致单核细胞库发生改变，导致促炎性 CD14+CD16+ 单核细胞亚群扩张和 T 淋巴细胞激活。此外，人们认识到HIV病毒因素可能会导致动脉粥样硬化。 HIV-1 Nef 蛋白通过下调 ATP 结合盒转运蛋白 A1 (ABCA1) 来损害巨噬细胞中胆固醇的流出，从而促进泡沫细胞的形成。我们假设这些免疫改变和病毒因素促进了艾滋病毒患者动脉粥样硬化的发展。为了进一步解决这些问题，我们将研究急性艾滋病毒感染期间患者动脉粥样硬化的早期措施，并在长期艾滋病毒感染期间纵向跟踪这些措施，假设在急性感染期间，当病毒负荷达到峰值时，血管内皮会发生促动脉粥样硬化变化。此外，为了研究潜在的机制，我们将利用从急性 HIV 感染时开始跟踪的这一纵向患者队列来研究 HIV 对单核细胞和 T 细胞的促炎改变以及 HIV nef 蛋白对 ABCA1 损伤的作用，作为我们假设的 HIV 感染与动脉粥样硬化之间关系的潜在关键机制。我们进一步假设他汀类药物治疗将减少 HIV 患者的斑块炎症并对促炎单核细胞和 T 淋巴细胞反应具有免疫调节作用。阐明他汀类药物引起的相关动脉粥样硬化指数将有助于指导未来的预防和靶向治疗策略，以减少该人群的心血管疾病。拟议的拨款将研究艾滋病毒病毒和免疫系统的相关变化对急性艾滋病毒感染期间和抗逆转录病毒治疗抑制病毒后动脉粥样硬化发展的影响。此外，还将在患有早期无症状动脉粥样硬化的艾滋病毒患者中研究降胆固醇药物对血管炎症和免疫细胞的潜在有益影响。 （摘要完）