Exosome in Methamphetamine and HIV-associated Neurodegeneration

 描述（由申请人提供）：外泌体在甲基苯丙胺和HIV相关的神经变性摘要外泌体是一类细胞外囊泡，已被指示为细胞间通讯的新兴介质。存在于来源于HIV感染细胞的外来体中的病毒分子被认为是细胞间病毒传播的关键传递物，代表了受体非依赖性感染模式（“特洛伊外来体假说”）。然而，来自HIV感染细胞的外泌体是否能够穿过血脑屏障（BBB）并靶向脑病毒库，特别是在精神兴奋剂药物的背景下，仍不清楚。我们的早期研究表明，甲基苯丙胺（METH）可以调节多种HIV细胞内限制因子的表达，从而损害宿主细胞的先天免疫。最近，我们发现，从免疫致敏的脑微血管内皮细胞（BMVEC）释放的外泌体能够整合，将功能性RNA/蛋白质转移到巨噬细胞并抑制HIV复制。基于这些早期的研究，我们假设METH可以损害BMVEC的先天免疫，从而影响外泌体介导的免疫调节活性从BBB到单核细胞的水平传递，促进HIV传播到大脑并导致神经变性。我们提出了三个具体目标来解决这些假设：目标1。确定METH对BMVEC的外泌体miRNA谱的影响以及这种调节如何影响单核细胞活化和对HIV感染的易感性;目的2.检查来源于HIV感染的巨噬细胞的外泌体在METH使用的背景下对BBB完整性和神经变性的作用;目的3。描述有或无HIV感染的METH使用者的血浆外泌体miRNA特征，并验证其在中枢神经系统（CNS）稳态调节中的功能意义。本研究的体外和体内系统数据将在 临床相关的和重要的，我们的理解的作用，外来体在脑内稳态。它在开发血浆外泌体miRNA签名作为METH和/或HIV相关神经变性的生物标志物方面也是重要的。

 DESCRIPTION (provided by applicant): Exosome in Methamphetamine and HIV-associated Neurodegeneration Abstract Exosomes are a class of extracellular vesicles that have been indicated as emerging mediators of cell-to- cell communication. Viral molecules present in exosomes derived from HIV-infected cells have been implicated as critical transmitters of intercellular viral spread, representing a receptor-independent mode of infection ("Trojan exosome hypothesis"). However, whether exosomes from HIV-infected cells are able to cross blood-brain barrier (BBB) and target brain viral reservoirs, particularly in the context of psychostimulant drugs, remains unclear. Our early studies showed that methamphetamine (METH) could modulate the expression of a variety of HIV intracellular restriction factors, thus compromising host cell innate immunity. Recently, we revealed that exosomes released from immune-primed brain microvascular endothelial cells (BMVEC) are able to incorporate, transfer functional RNA/proteins to macrophages and suppress HIV replication. Based on these earlier studies, we hypothesize that METH can compromise the innate immunity of BMVEC, thus affecting exosome-mediated horizontal transmission of immunoregulatory activity from BBB to monocytes, facilitating HIV dissemination to brain and resulting in neurodegeneration. We propose three specific aims to address these hypotheses: Aim 1. To determine the effect of METH on exosomal miRNA profile of BMVEC and how this modulation affects monocyte activation and susceptibility to HIV infection; Aim 2. To examine the role of exosomes derived from HIV-infected macrophages on BBB integrity and neurodegeneration in the context of METH use; Aim 3. To characterize plasma exosomal miRNA signatures of METH users with or without HIV infection and validate their functional significance in central nervous system (CNS) homeostatic regulation. Data arising from this study with both in vitro and in vivo systems will be clinically relevant and important to our understanding of the role of exosomes in brain homeostasis. It is also significant in terms of developing plasma exosomal miRNA signature as a biomarker for METH- and/or HIV-associated neurodegeneration.