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

摘要 艾滋病毒感染伴随着许多共病，心脏代谢并发症是其中之一 最突出的。目前的抗逆转录病毒疗法(ART)可以控制艾滋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共病。导致心脏持续存在的机制- 接受抗逆转录病毒治疗的HIV感染者在无法检测到病毒载量的情况下，代谢共病仍不清楚， 阻碍治疗方法的发展。我们的研究确定了HIV蛋白Nef是主要的 病毒对胆固醇代谢和潜在心脏表型影响的贡献者。其他最近来自 几个研究小组证明，感染艾滋病毒的细胞释放含有Nef的细胞外小泡(EVS)，Nef 在接受抗逆转录病毒治疗的艾滋病毒感染者中，约有50%的人在无法检测到病毒载量的血浆中发现了这种病毒。我们 显示含有Nef的EV，但不是由感染Nef缺陷的HIV的细胞产生的EV，触发 未感染的巨噬细胞中细胞胆固醇代谢的扰动，丰度增加和改变 这些细胞中的脂筏的特性，并导致炎症反应的增强。这些发现导致了 我们同意一种假说，即Nef Evs诱导的脂筏变化可能是心血管疾病发生机制的基础。 HIV疾病的代谢并存，因此这些并存可以通过阻断药物来治疗 或逆转Nef引起的脂筏改变。我们将这种治疗方法命名为脂筏疗法。在 建议的项目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EVS对脂筏的成分和结构的影响，并与 这些对功能属性的更改。我们还将确定阻断Nef EVS效果的治疗是否 脂筏上可逆转Nef诱导的功能效应。在目标2中，我们将调查两者之间的关联 NEF EVS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apoE-/-小鼠转基因HIV或感染小鼠HIV(EcoHIV)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 艾滋病毒携带者(PLWH)与心脏代谢共病的标志物相关，无论是血液 PLWH的单核细胞出现脂筏变化，这些变化能否在体外被脂质逆转 RAFT疗法在AIMS 1和AIMS 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 并将研究针对这一机制的新的治疗方法，从而产生 基础科学和翻译领域的影响。

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.