HIV and substances of abuse influence exosomes and endothelial cell function

 描述(申请人提供)：艾滋病毒感染会导致中枢神经系统并发症，近75%的晚期艾滋病毒患者表现出亚临床到临床的神经症状。其他后遗症还有长期成功接受CART治疗的患者，他们患有艾滋病毒感染的残留和终末期器官疾病。内皮细胞功能障碍是HIV神经发病机制的核心。血脑屏障受损会导致白细胞迁移增加、艾滋病毒感染和高度炎症环境的建立，从而进一步加重艾滋病毒相关的神经疾病。几乎所有类型的细胞都会分泌微泡。存在许多类型，我们将统称为外体。这些病毒在HIV患者的血液中循环。它们影响本地和远离其蜂窝来源的站点的细胞间通信。血管内皮细胞、淋巴管内皮细胞和屏障内皮细胞可能比任何其他类型的细胞更容易接触到循环中的外切体。HIV感染会影响外切体的组成，并利用这些小泡促进病毒的发病和传播。来自受感染细胞的外切体可以含有病毒蛋白、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的发病。我们在HIV相关癌症患者和动物模型中循环的外切体显示了这一点(Chugh等人。PLOS帕索格。2013年；9(7)：e1003484)。包括可卡因和类大麻在内的滥用药物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发展，并导致与艾滋病毒有关的神经并发症。几项研究已经证明，这些药物独立地引发内皮细胞功能的明显变化。然而，滥用药物对外切体的生产、组成和功能的影响，特别是在艾滋病毒感染的背景下，代表了我们认识的一个重大差距。因此，迫切需要了解外切体在HIV发病机制中的作用，以及药物使用等可能影响HIV外切体诱导的细胞间通讯的因素。这也可能导致确定潜在的治疗靶点，以阻断特定的外体货物和/或可能促进疾病进展的内皮细胞的下游效应。此R01应用程序旨在解决HIV感染细胞的外切体如何影响血脑屏障通透性和内皮细胞功能障碍，以及滥用药物可能如何影响外切体的货物和功能。

 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.