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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：
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.

摘要