HIV neuropathogenesis related to exosomes containing HIV non-coding RNAs

与含有 HIV 非编码 RNA 的外泌体相关的 HIV 神经发病机制

• 批准号: 9893927
• 负责人: Fatah Kashanchi
• 金额: $ 37.7万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893927
• 关键词: AIDS dementia; Acquired Immunodeficiency Syndrome; Active Sites; Acute; Adhesions; Affect; Asses; Astrocytes; Autoimmunity; Biogenesis; Blood; Blood - brain barrier anatomy; Brain; Cell Line; Cells; Cessation of life; Chronic; Clinical; Collection; Data; Disease; Double-Stranded RNA; Elements; Environment; Evolution; Face; Failure; Gene Expression; Gene Expression Regulation; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Life Expectancy; Malignant Neoplasms; Membrane; Membrane Proteins; Meningeal; Meninges; Messenger RNA; Metalloproteases; MicroRNAs; Microglia; Modeling; Neurocognitive Deficit; Neurologic Deficit; Neuropathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Play; Premature aging syndrome; Production; Proteins; RNA; Research; Risk; Role; Signal Transduction; Site; Stroke; Surface; Syndrome; T-Lymphocyte; TLR3 gene; Testing; Time; Untranslated RNA; Vesicle; Viral; Viral Load result; Virus; Virus Replication; antiretroviral therapy; base; brain parenchyma; cell type; cytokine; exosome; humanized mouse; immune reconstitution; in vitro Model; in vivo; inhibitor/antagonist; intercellular communication; macrophage; mouse model; nervous system disorder; pandemic disease; protein biomarkers; public health relevance; receptor; uptake; viral RNA; virology; virus host interaction; AIDS dementia; Acquired Immunodeficiency Syndrome; Active Sites; Acute; Adhesions; Affect; Asses; Astrocytes; Autoimmunity; Biogenesis; Blood; Blood - brain barrier anatomy; Brain; Cell Line; Cells; Cessation of life; Chronic; Clinical; Collection; Data; Disease; Double-Stranded RNA; Elements; Environment; Evolution; Face; Failure; Gene Expression; Gene Expression Regulation; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Life Expectancy; Malignant Neoplasms; Membrane; Membrane Proteins; Meningeal; Meninges; Messenger RNA; Metalloproteases; MicroRNAs; Microglia; Modeling; Neurocognitive Deficit; Neurologic Deficit; Neuropathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Play; Premature aging syndrome; Production; Proteins; RNA; Research; Risk; Role; Signal Transduction; Site; Stroke; Surface; Syndrome; T-Lymphocyte; TLR3 gene; Testing; Time; Untranslated RNA; Vesicle; Viral; Viral Load result; Virus; Virus Replication; antiretroviral therapy; base; brain parenchyma; cell type; cytokine; exosome; humanized mouse; immune reconstitution; in vitro Model; in vivo; inhibitor/antagonist; intercellular communication; macrophage; mouse model; nervous system disorder; pandemic disease; protein biomarkers; public health relevance; receptor; uptake; viral RNA; virology; virus host interaction

 DESCRIPTION (provided by applicant): Nearly one third of HIV-infected individuals develop neurocognitive deficits despite adequate cART and excellent virological control in the blood. This range of neurocognitive deficits is collectively referred to as HIV-1-associated neurocognitive disorders (HAND). Virus may also enter the brain again in the later stages of infection when there is a general immune failure. The ability of the virus to replicate depends on the cell type and its state of activation. Once inside the brain parenchyma, it resides in perivascular macrophages and microglial cells that provide the site of productive replication and evolution for HIV. Recent studies suggest that there is a substantial viral load in the meninges as well where there is a rich collection of macrophages. Within these regions, HIV infects the macrophages/microglia and astrocytes most commonly located in the perivascular regions where they constitute the blood-brain barrier. Perivascular and meningeal macrophages have been shown to be sites of active viral replication in the human brain. Exosomes are membrane-bound vesicles produced by a variety of cells that contain classical membrane marker proteins such as tetraspanins, adhesion proteins and metalloproteinases. They are considered to play an important role in intercellular communication either by target cell uptake or by inducing cell signaling via membrane receptors. In addition to membrane proteins, exosomes carry mRNAs as well as non-coding RNAs, including miRNAs that are thought to affect gene regulation in the target cells. Research by our group and others has shown that HIV-1-infected cells produce exosomes that activate naïve target cells through a dsRNA called TAR. Our long term goal is to understand the role played by exosomes originating from HIV-1 infected cells in regulating host-virus interactions. We hypothesize that unique viral RNA present in the exosomes of infected cells will alter recipient cells impacting regulation of gene expression and establishment of inflammatory response. Our aims include: To characterize the biogenesis and function of exosomes from infected donor cells under cART (Aim I); To characterize exosomes from infected cells treated with inhibitors and their cellular origin (Aim II), and defining the mechanim of TAR effect on TLR modulation and cytokine production in recipient cells. Collectively our data indicates that infected cells under cART still secrete TAR associated exosmes and that these exosomes activate the naïve recipient cells resulting in unwanted proinflammatory signals. These activities will be reversed with use of inhibitors and tested in both an in vitro BBB model and humanized latent model of HIV infection.

 描述（由适用提供）：尽管有足够的手推车和血液中出色的病毒学控制，近三分之一的HIV感染者仍会发展神经认知缺陷。这种神经认知能力范围统称为与HIV-1相关的神经认知障碍（HAND）。一般的免疫衰竭时，病毒也可能在感染的后期再次进入大脑。病毒复制的能力取决于细胞类型及其激活状态。一旦进入脑实质，它就会驻留在血管周围巨噬细胞和小胶质细胞中，这些细胞为HIV提供了生产性复制和进化的位点。最近的研究表明，脑膜上也存在大量巨噬细胞的大量病毒负荷。在这些地区，HIV感染巨噬细胞/小胶质细胞和星形胶质细胞最常见于它们构成血脑屏障的周围区域。血管周围和脑膜巨噬细胞已被证明是人脑中主动病毒复制的部位。外泌体是膜结合的蔬菜，这些蔬菜由多种细胞产生，这些细胞包含经典的膜标志物蛋白，例如四叠胶蛋白，粘合蛋白和金属蛋白酶。它们被认为在靶细胞摄取或通过膜受体诱导的细胞信号传导在细胞间通信中起重要作用。除膜蛋白外，外泌体携带mRNA和非编码RNA，包括被认为会影响靶细胞基因调节的miRNA。我们小组和其他人的研究表明，HIV-1感染的细胞通过称为TAR的DSRNA激活幼稚的靶细胞的外泌体。我们的长期目标是了解来自HIV-1感染细胞在调节宿主病毒相互作用中起源于HIV-1感染细胞的作用。我们假设感染细胞外泌体中存在的独特病毒RNA会改变影响基因表达调节和炎症反应的建立的受体细胞。我们的目的包括：表征来自手推车下感染供体细胞的外泌体的生物发生和功能（AIM I）；为了表征来自受抑制剂及其细胞起源治疗的感染细胞的外泌体（AIM II），并定义焦油对受体细胞中TLR调节和细胞因子产生的作用机理。我们的数据集体表明，在货车下仍有秘密焦油相关的外膜的感染细胞，这些外泌体激活了幼稚的受体细胞，从而导致不良的促炎信号。这些活性将通过使用抑制剂来逆转，并在体外BBB模型和HIV感染的人源性潜在模型中进行了测试。