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：
10254964
负责人：
MICHAEL Ilya BUKRINSKY
金额：
$ 69.35万
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/10254964
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 Human immunodeficiency virus test Immunologic Deficiency Syndromes Impairment Individual Inflammatory Response Insulin Resistance Lipids Measures Mediating Membrane Microdomains Metabolic Metabolic Diseases Methods Modeling Modification Mus Names Pathogenesis Pathogenicity Pathologic Pathway interactions Peripheral Blood Mononuclear Cell 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 macrophage 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.

抽象的艾滋病毒感染伴随着许多合并症，心脏代谢并发症之一最突出的。当前的抗逆转录病毒疗法（ART）控制HIV负荷并逆转免疫缺陷，但不会消除与HIV相关的合并症。导致心脏持续性的机制具有无法检测到的病毒负荷的ART治疗的HIV感染受试者的代谢合并症仍然未知，防止治疗治疗的发展。我们的研究确定HIV蛋白NEF是主要的病毒对胆固醇代谢和潜在心脏表型的影响。来自几个组表明，感染的HIV感染细胞释放含有NEF的细胞外蔬菜（EV），在约50％的ART治疗的患有无法检测的病毒载量的ART治疗的HIV感染的个体中，我们发现了我们。我们表明含有NEF的EV，而不是由NEF缺陷HIV感染的细胞产生的EV，触发的EVS 细胞胆固醇代谢在未感染的巨噬细胞中的扰动，抽象增加并改变这些细胞中脂质筏的特性，并导致炎症反应的潜力。这些发现引起了我们想到一个假设，即由NEF EV引起的脂质筏的变化可能是心脏机理的基础 HIV疾病的代谢合并症，因此可以通过阻塞的药物治疗这些合并症或逆转NEF诱导的脂质筏的变化。我们将这种治疗方法命名为“脂质筏疗法”。在拟议项目我们将通过追求以下特定目标来检验这一假设。在AIM 1中，我们将表征含NEF的EV对脂质筏的组成和结构的影响，并将与这些变化对功能性能。我们还将确定治疗是否阻止了NEF EV的影响在脂质筏上可以逆转NEF诱导的功能效应。在AIM 2中，我们将调查 NEF EV和心脏代谢合并症，将在体内测试脂质筏靶向治疗方法。我们将使用apoE - / - 小鼠转基因进行HIV或感染鼠HIV（ECOHIV）来建模HIV相关动脉粥样硬化和代谢障碍。在AIM 3中，我们将确定在等离子体中的EXNEF水平是否患有艾滋病毒（PLWH）的人与心脏代谢合并症的标记相关，是否血液 PLWH的单核细胞表现出脂质筏的变化，以及这些变化是否可以通过脂质反转在目标1和2中测试的筏疗法。一起，这些研究将描述与HIV相关的新机制合并症，并将研究针对该机制的新的治疗方法，从而产生基础科学和对该领域的翻译影响。