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Lipid raft therapy – a novel therapeutic approach for HIV-associated cardiometabolic co-morbidities

脂筏疗法 — 一种治疗 HIV 相关心脏代谢并发症的新方法

基本信息

批准号：
10599899
负责人：
MICHAEL Ilya BUKRINSKY
金额：
$ 63.4万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-09 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599899
关键词：
Affect Apolipoprotein A-I Apolipoprotein E Apoptosis Atherosclerosis Basic Science Binding Proteins Blood Blood Cells Cardiac Cardiometabolic Disease Cardiovascular Diseases Cell membrane Cells Cellular Metabolic Process Chemosensitization Cholesterol Homeostasis Development Disease Elements Exhibits HIV HIV Infections Immunologic Deficiency Syndromes Impairment Individual Inflammatory Response Insulin Resistance Lipids Macrophage Measures Mediating Membrane Microdomains Metabolic Metabolic Diseases Methods Modeling Modification Mus Names Pathogenesis Pathogenicity Pathologic Pathway interactions Peripheral Blood Mononuclear Cell Persons Phenotype Plasma Play Predisposition Property Reporting Role Signal Transduction Structure Testing Therapeutic Transgenic Mice Transgenic Organisms Viral Viral Load result Viral Proteins Viral load measurement Viral reservoir Virus antiretroviral therapy carbohydrate metabolism cardiometabolism comorbidity extracellular vesicles high risk in vivo inflammatory marker lipid metabolism lipid transport monocyte mouse model nef Protein novel novel therapeutic intervention novel therapeutics prevent recruit targeted treatment therapeutic development therapeutic target therapy design translational impact treatment strategy vesicular release

项目摘要

Abstract HIV infection is accompanied by a number of co-morbidities, with cardio-metabolic complications being among the most prominent. Current antiretroviral therapy (ART) controls the HIV load and reverses immunodeficiency, but does not eliminate HIV-associated co-morbidities. The mechanisms responsible for the persistence of cardio- metabolic co-morbidities in ART-treated HIV-infected subjects with an undetectable virus load remain unknown, preventing the development of therapeutic treatments. Our studies identified HIV protein Nef as the main contributor to viral effects on cholesterol metabolism and potential cardiac phenotypes. Other recent reports from several groups demonstrated that HIV-infected cells release extracellular vesicles (EVs) containing Nef, which were found in the plasma of ~50% of ART-treated HIV-infected individuals with undetectable viral load. We showed that Nef-containing EVs, but not EVs produced by cells infected with Nef-deficient HIV, triggered perturbations of cellular cholesterol metabolism in uninfected macrophages, increased abundance and changed the properties of lipid rafts in these cells, and led to potentiation of inflammatory responses. These findings led us to a hypothesis that changes to lipid rafts induced by Nef EVs may underlie the mechanism of cardio- metabolic co-morbidities of HIV disease, and therefore these co-morbidities can be treated by agents blocking or reversing the Nef-induced changes of lipid rafts. We named this treatment approach “lipid raft therapy”. In the proposed project we will test this hypothesis by pursuing the following Specific Aims. In Aim 1, we will characterize the effects of Nef-containing EVs on the composition and structure of the lipid rafts and will relate these changes to functional properties. We will also determine whether treatments blocking the effect of Nef EVs on lipid rafts can reverse the Nef-induced functional effects. In Aim 2, we will investigate the association between Nef EVs and cardio-metabolic co-morbidities and will test lipid raft-targeting treatment approaches in vivo. We will use apoE-/- mice transgenic for HIV or infected with murine HIV (EcoHIV) to model HIV-associated atherosclerosis and metabolic impairment. In Aim 3, we will determine whether levels of exNef in plasma of people living with HIV (PLWH) correlate with markers of cardio-metabolic co-morbidities, whether blood monocytes of PLWH exhibit lipid rafts changes, and whether these changes can be reversed ex vivo by the lipid raft therapy tested in Aims 1 and 2. Together, these studies will describe a new mechanism of HIV-associated co-morbidities and will investigate new therapeutic treatments targeting this mechanism, thus producing both a basic science and a translational impact on the field.

抽象的 HIV 感染会伴有许多并发症，其中包括心脏代谢并发症最突出的。目前的抗逆转录病毒疗法（ART）可以控制艾滋病病毒载量并逆转免疫缺陷，但并不能消除与艾滋病毒相关的并发症。负责心脏持续的机制经 ART 治疗且病毒载量无法检测到的 HIV 感染者的代谢合并症仍然未知，阻碍治疗方法的发展。我们的研究确定 HIV 蛋白 Nef 是主要的导致病毒对胆固醇代谢和潜在心脏表型的影响。其他最近的报告来自多个研究小组证明，HIV 感染细胞会释放含有 Nef 的细胞外囊泡 (EV)，在约 50% 接受 ART 治疗的 HIV 感染者的血浆中发现了病毒载量无法检测到的病毒。我们表明含有 Nef 的 EV，而不是由感染 Nef 缺陷的 HIV 的细胞产生的 EV，触发了未感染巨噬细胞中细胞胆固醇代谢的扰动，丰度增加并发生变化这些细胞中脂筏的特性，并导致炎症反应增强。这些发现导致我们假设 Nef EV 引起的脂筏变化可能是心血管机制的基础 HIV 疾病的代谢合并症，因此这些合并症可以通过阻断药物来治疗或逆转 Nef 诱导的脂筏变化。我们将这种治疗方法命名为“脂筏疗法”。在在拟议的项目中，我们将通过追求以下具体目标来检验这一假设。在目标 1 中，我们将描述含有 Nef 的 EV 对脂筏的组成和结构的影响，并将与这些功能属性的变化。我们还将确定治疗是否会阻止 Nef EV 的作用对脂筏的作用可以逆转 Nef 诱导的功能效应。在目标 2 中，我们将研究之间的关联 Nef EV 和心脏代谢并发症，并将在体内测试脂筏靶向治疗方法。我们将使用 HIV 转基因 apoE-/- 小鼠或感染小鼠 HIV (EcoHIV) 的小鼠来建立 HIV 相关模型动脉粥样硬化和代谢障碍。在目标 3 中，我们将确定血浆中 exNef 的水平是否 HIV 感染者 (PLWH) 与心脏代谢合并症的标志物相关，无论是血液 PLWH的单核细胞表现出脂筏变化，以及这些变化是否可以通过脂质在体外逆转筏疗法在目标 1 和 2 中进行了测试。这些研究将共同描述 HIV 相关的一种新机制共病并将研究针对该机制的新治疗方法，从而产生基础科学以及对该领域的转化影响。