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

 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（由申请人提供）：尽管有足够的 cART 和良好的血液病毒学控制，但仍有近三分之一的 HIV 感染者出现神经认知缺陷。这种神经认知缺陷统称为 HIV-1 相关神经认知障碍 (HAND)。当普遍的免疫失败时，病毒也可能再次进入大脑。病毒的复制能力取决于细胞类型及其进入大脑后的激活状态。最近的研究表明，脑膜中也存在大量的病毒，这些区域内也有丰富的巨噬细胞。 HIV感染的巨噬细胞/小胶质细胞和星形胶质细胞最常位于构成血脑屏障的血管周围区域，血管周围和脑膜巨噬细胞已被证明是病毒复制活跃的部位。外泌体是由多种细胞产生的膜结合囊泡，含有经典的膜标记蛋白，例如四跨膜蛋白、粘附蛋白和金属蛋白酶，它们被认为通过靶细胞摄取或诱导在细胞间通讯中发挥重要作用。除了膜蛋白外，外泌体还携带 mRNA 和非编码 RNA，包括我们小组研究的被认为影响靶细胞基因调控的 miRNA。等人表明，HIV-1 感染的细胞产生外泌体，通过称为 TAR 的 dsRNA 激活初始靶细胞。我们的长期目标是了解源自 HIV-1 感染细胞的外泌体在调节宿主病毒相互作用中所发挥的作用。我们寻求感染细胞外泌体中存在的独特病毒 RNA 将改变受体细胞，影响基因表达的调节和炎症反应的建立。我们的目标包括： 表征 cART 下受感染供体细胞外泌体的生物发生和功能。 （目标 I）；表征受感染细胞的外泌体及其细胞来源（目标 II），并确定 TAR 对受体细胞中 TLR 调节和细胞因子产生的影响机制。分泌 TAR 相关的外泌体，这些外泌体会激活初始受体细胞，从而产生不需要的促炎信号，并在体外 BBB 模型和人源化潜在模型中进行测试。艾滋病毒感染。

项目成果

Exosomes as New Players in HIV Pathogenesis - New Data from the IAS 2017.

外泌体作为 HIV 发病机制的新参与者 - 来自 IAS 2017 的新数据。

• 发表时间: 2017
• 影响因子: 2.2
• 作者: Poveda, Eva;Freeman, Michael L
• 通讯作者: Freeman, Michael L

Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread.

HTLV-1 感染细胞的细胞外囊泡调节靶细胞和病毒传播。

• 发表时间: 2021-02-23
• 影响因子: 3.3
• 作者: Pinto, Daniel O;Al Sharif, Sarah;Mensah, Gifty;Cowen, Maria;Khatkar, Pooja;Erickson, James;Branscome, Heather;Lattanze, Thomas;DeMarino, Catherine;Alem, Farhang;Magni, Ruben;Zhou, Weidong;Alais, Sandrine;Dutartre, Hélène;El;Mah
• 通讯作者: Mah

Author Correction: Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation.

作者更正：在小鼠大脑中鼻内递送小干扰 RNA 药物，靶向用聚乙烯亚胺 (PEI) 封装的 Beclin1，以实现 HIV 衰减。

• 发表时间: 2018-03-14
• 影响因子: 4.6
• 作者: Rodriguez, Myosotys;Lapierre, Jessica;Ojha, Chet Raj;Kaushik, Ajeet;Batrakova, Elena;Kashanchi, Fatah;Dever, Seth M;Nair, Madhavan;El
• 通讯作者: El

Exosomes in Viral Disease.

病毒疾病中的外泌体。

• 发表时间: 2016-07
• 作者: Anderson, Monique R;Kashanchi, Fatah;Jacobson, Steven
• 通讯作者: Jacobson, Steven

Corrigendum: Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction.

勘误表：外泌体中的埃博拉 VP40 可导致免疫细胞功能障碍。

• 发表时间: 2018
• 作者: Pleet, Michelle L;Mathiesen, Allison;DeMarino, Catherine;Akpamagbo, Yao A;Barclay, Robert A;Schwab, Angela;Iordanskiy, Sergey;Sampey, Gavin C;Lepene, Benjamin;Ilinykh, Philipp A;Bukreyev, Alexander;Nekhai, Sergei;Aman, M Javad;Kashanchi, Fata
• 通讯作者: Kashanchi, Fata