HIV and substances of abuse influence exosomes and endothelial cell function

 描述（由申请方提供）：HIV感染导致CNS并发症，近75%的晚期HIV疾病患者显示亚临床至临床神经系统表现。其他后遗症包括长期成功接受cART治疗的患者，他们患有HIV感染的残留和终末器官疾病。内皮细胞功能障碍是HIV神经发病机制的核心。受损的血脑屏障导致白细胞迁移增加、HIV感染和高度炎症环境的建立，这进一步加重了HIV相关的神经系统疾病。微泡几乎从每种细胞类型中分泌。存在许多类型，我们将其统称为外泌体。它们在艾滋病患者的血液中循环。它们影响细胞间的通讯在本地和远程网站从他们的细胞来源。血管、淋巴和屏障内皮细胞可能比任何其他细胞类型都更经常地暴露于循环外泌体。HIV感染可以影响外泌体的组成，并利用这些囊泡促进病毒的发病和传播。来自感染细胞的外来体可以包含病毒蛋白、宿主microRNA和触发内皮细胞反应的蛋白质，所有这些都可以促进HIV发病机制。我们针对在HIV相关癌症患者和动物模型中循环的外来体显示了这一点（Chugh等人，PLoS Pathog. 2013;9（7）：e1003484）。滥用药物，包括可卡因和cannibinoids与艾滋病毒风险增加有关，这些物质可能不利于艾滋病毒的进展，并导致艾滋病毒相关的神经系统并发症。一些研究已经证明，这些药物独立地触发内皮细胞功能的不同变化。然而，药物滥用对外来体产生、组成和功能的影响，特别是在艾滋病毒感染的情况下，代表了我们知识中的一个重大空白。因此，迫切需要了解外泌体在HIV发病机制中的作用以及可能影响HIV外泌体诱导的细胞间通讯的因素，如药物使用。这也可能导致鉴定潜在的治疗靶点，以阻断内皮细胞中可能促进疾病进展的特异性外泌体货物和/或下游效应。该R 01申请旨在解决来自HIV感染细胞的外泌体如何影响血脑屏障通透性和内皮细胞功能障碍，以及滥用药物如何影响外泌体的货物和功能。

 DESCRIPTION (provided by applicant): HIV infection results in CNS complications, with nearly 75% of patients with advanced HIV disease showing subclinical to clinical neurological manifestations. Additional sequelae have patients on long-term successful cART therapy who suffer from residual and end organ diseases of HIV infection. Endothelial cell dysfunction is central to HIV neuropathogenesis. A compromised blood brain barrier results in increased leukocyte transmigration, HIV infection, and the establishment of a highly inflammatory environment, which further aggravates HIV-associated neurological disease. Microvesicles are secreted from nearly every cell type. Many types exist, which we shall refer to collectively as exosomes. These circulate in the bloodstream of HIV patients. They influence intercellular communication at both local and distant sites from their cellular source. Vascular, lymphatic, and barrier endothelial cells, perhaps more than any other cell type, are constantly exposed to circulating exosomes. HIV infection can affect the composition of exosomes and utilizes these vesicles to facilitate viral pathogenesis and spread. Exosomes from infected cells can contain viral proteins, host microRNAs and proteins that trigger responses in endothelial cells, all of which can promote HIV pathogenesis. We showed this for exosomes circulating in HIV associated cancer patients and animal models (Chugh et al. PLoS Pathog. 2013;9(7):e1003484). Drugs of abuse including cocaine and cannibinoids are associated with increased HIV risk and these substances can be detrimental to HIV progression and contribute to HIV-associated neurological complications. Several studies have demonstrated that these drugs independently trigger distinct changes in endothelial cell function. However, the influence of drugs of abuse on exosome production, composition and function, especially in the context of HIV infection, represents a significant gap in our knowledge. Therefore, there is a critical need to understand the role of exosomes in HIV pathogenesis and factors that may influence HIV exosome-induced intercellular communication such as drug use. This may also lead to identification of potential therapeutic targets to block specific exosomal cargo and/or downstream effects in endothelial cells that may promote disease progression. This R01 application seeks to address how exosomes from HIV-infected cells affect blood brain barrier permeability and endothelial cell dysfunction and how drugs of abuse may influence exosomal cargo and function.