HIV and substances of abuse influence exosomes and endothelial cell function

HIV 和滥用物质影响外泌体和内皮细胞功能

• 批准号: 9304176
• 负责人: Dirk P Dittmer
• 金额: $ 37.05万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304176
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Animal Model; Animals; Behavioral; Behavioral Sciences; Biogenesis; Biological; Biological Assay; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Cancer Patient; Cannabinoids; Cell Line; Cell physiology; Cells; Cellular biology; Clinical; Clinical Sciences; Cocaine; Cocaine Abuse; Data; Development; Disease; Disease Progression; Distant; Drug usage; Endothelial Cells; Exposure to; Extravasation; Functional disorder; HIV; HIV Infections; HIV risk; Human; Inflammatory; Intervention; Knowledge; Lead; Leukocytes; Liposomes; Liquid substance; Lymphatic; Lymphatic Endothelial Cells; Malignant Neoplasms; Mediator of activation protein; Methods; MicroRNAs; Neurologic; Neurologic Symptoms; Neuropathogenesis; Organ; Pathogenesis; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Process; Production; Proteins; Research; Research Personnel; Residual Tumors; Residual state; Risk; Role; Signal Transduction; Site; Source; Structure; Substance abuse problem; Substance of Abuse; System; Testing; Tight Junctions; Vesicle; Viral Pathogenesis; Viral Proteins; Work; biobank; cell behavior; cell growth; cell type; cofactor; cytokine; drug of abuse; exosome; experience; extracellular vesicles; humanized mouse; in vivo; in vivo Model; inflammatory milieu; innovation; insight; intercellular communication; microvesicles; mouse model; nervous system disorder; novel; novel marker; pathogen; public health relevance; response; therapeutic target; tool; uptake

 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.

 描述（由申请人提供）：HIV 感染会导致中枢神经系统并发症，近 75% 的晚期 HIV 患者表现出亚临床到临床的神经系统表现。其他后遗症包括接受长期成功的 cART 治疗的患者患有 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。血脑屏障受损会导致白细胞迁移增加、艾滋病毒感染以及高度炎症环境的建立，从而进一步加剧艾滋病毒相关的神经系统疾病。几乎所有细胞类型都会分泌微泡。存在多种类型，我们将其统称为外泌体。它们在艾滋病毒患者的血液中循环。它们影响本地和远离细胞来源的细胞间通讯。血管、淋巴和屏障内皮细胞可能比任何其他细胞类型都更多地持续暴露于循环外泌体。 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。来自受感染细胞的外泌体可能含有病毒蛋白、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 发病机制。我们在 HIV 相关癌症患者和动物模型中循环的外泌体中展示了这一点（Chugh 等人 PLoS Pathog. 2013;9(7):e1003484）。包括可卡因和大麻素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进展，并导致艾滋病毒相关的神经并发症。多项研究表明，这些药物独立地引发内皮细胞功能的明显变化。然而，滥用药物对外泌体产生、组成和功能的影响，特别是在艾滋病毒感染的情况下，代表了我们的知识上的重大差距。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（例如药物使用）的因素。这也可能导致识别潜在的治疗靶点，以阻断特定的外泌体货物和/或内皮细胞中可能促进疾病进展的下游效应。该 R01 申请旨在解决 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。