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

摘要 艾滋病毒感染伴随着一些合并症，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）控制艾滋病毒载量和逆转免疫缺陷， 但不能消除HIV相关的合并症。负责心血管持续性的机制- ART治疗的HIV感染受试者中的代谢共病与不可检测的病毒载量仍然未知， 阻碍了治疗方法的发展。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。其他最近的报告， 几个研究小组证明，HIV感染的细胞释放含有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，病毒载量检测不到。我们 结果显示，含有Nef的EV，而不是由Nef缺陷型HIV感染的细胞产生的EV， 未感染巨噬细胞中细胞胆固醇代谢紊乱，丰度增加， 这些细胞中脂筏的性质，并导致炎症反应的增强。基于这些发现得出 我们假设Nef EV诱导的脂筏变化可能是心血管疾病机制的基础。 HIV疾病的代谢共病，因此这些共病可以通过阻断HIV代谢的药物来治疗。 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 我们将通过追求以下具体目标来验证这一假设。在目标1中，我们 表征含Nef的EV对脂筏的组成和结构的影响，并将涉及 这些功能特性的变化。我们还将确定阻断Nef EV效应的治疗是否 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 Nef EV和心脏代谢共病，并将在体内测试脂筏靶向治疗方法。我们 将使用HIV转基因或感染鼠HIV（EcoHIV）的apoE-/-小鼠来模拟HIV相关的 动脉粥样硬化和代谢损伤。在目标3中，我们将确定是否血浆中exNef的水平， 艾滋病毒感染者（PLWH）与心脏代谢共病的标志物相关，无论是血液 PLWH的单核细胞表现出脂筏的变化，以及这些变化是否可以通过脂质逆转离体 在目标1和2中测试了筏式疗法。总之，这些研究将描述一种新的机制， 并将研究针对这一机制的新的治疗方法，从而产生一种 基础科学和对该领域的转化影响。

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.