Engineered exosomes target inflammation in HIV

工程外泌体靶向 HIV 炎症

• 批准号: 9617614
• 负责人: Lynn PULLIAM
• 金额: $ 24.45万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9617614
• 关键词: Anti-Retroviral Agents; Biological Markers; Brain; C-reactive protein; CD14 gene; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cells; Chronic; Clinical; Comorbidity; Cytoplasm; Encapsulated; Engineering; Extracellular Space; FCGR3B gene; Genes; HIV; HIV Infections; Health; Immune; Immune response; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferon-alpha; Interferons; Lipids; Lipopolysaccharides; Membrane; Messenger RNA; Metabolic; MicroRNAs; Outcome; Parents; Pathologic; Pathology; Pattern; Peripheral; Phenotype; Physiological; Play; Process; Proteins; Role; Untranslated RNA; Vesicle; Viral; Viral reservoir; Work; acute infection; antiretroviral therapy; base; cytokine; effective therapy; exosome; experience; humanized mouse; immune activation; immune function; improved; in vitro Assay; in vivo; macrophage; monocyte; mouse model; nanoparticle; response

Chronic immune activation persists in a subset of HIV-infected individuals who are virally suppressed. The consequences of this activation include cognitive impairment, cardiovascular disease and metabolic abnormalities. While a functioning immune response is important to maintain good health, continued activation can be detrimental. Our work has concentrated on monocyte activation in HIV infection and the initiation as well as consequences of chronic immune activation, including cognitive impairment and downstream cellular effects. Interferon alpha (IFNα) and lipopolysaccharide (LPS) from HIV infection activate monocytes that release exosomes, which are membrane bound nanoparticles that contain functional proteins, mRNA and abundant small noncoding microRNAs (miR). These exosomes alone can enter and influence recipient cells. We have characterized the exosomes from activated monocytes and identified miRs that influence immune activation associated with HIV infection. Our overall hypothesis is that targeted exosomes carrying specific antagomiRs will decrease peripheral activation and may decrease HIV infection by silencing activated monocytes. This proposal will engineer exosomes targeted to CD16+ monocytes and containing antagomiRs to silence the activation associated with several miRs that cause downstream brain and cardiovascular inflammation. We will utilize a functional in vitro assay to confirm silencing. Once we identify antagomiRs that can effectively silence the inflammatory response we will use these targeted exosomes in a humanized HIV mouse model and evaluate the in vivo response.

慢性免疫激活在一部分通过病毒感染的艾滋病毒感染者身上持续存在 被压制了。这种激活的后果包括认知障碍， 心血管疾病和代谢异常。当一个正常运作的免疫系统 反应对保持良好的健康很重要，持续的激活可能是有害的。 我们的工作集中在单核细胞在HIV感染中的激活和启动AS 以及慢性免疫激活的后果，包括认知障碍和 下游细胞效应。干扰素α和脂多糖 HIV感染激活单核细胞，释放膜结合的外体 含有功能性蛋白质、信使核糖核酸和丰富的小分子非编码的纳米颗粒 MicroRNAs(MiR)只有这些外切体才能进入并影响受体细胞。我们 已经表征了激活的单核细胞的外切体，并鉴定了MIR 影响与艾滋病毒感染相关的免疫激活。我们的总体假设是 携带特定抗核抗体的靶向外体将减少外周血的激活和 可能通过沉默激活的单核细胞来减少HIV感染。这项提议将 以CD16+单核细胞为靶标并含有沉默对映体的工程外体 与几个MIR相关的激活导致下游大脑和 心血管炎症。我们将利用一种功能性的体外试验来证实 沉默。一旦我们确定了可以有效平息炎症的对抗剂 我们将在人源化的HIV小鼠模型中使用这些靶向外切体 评估体内反应。