Engineered exosomes target inflammation in HIV

工程外泌体靶向 HIV 炎症

基本信息

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
项目类别：
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

项目摘要

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.

慢性免疫激活在病毒感染的艾滋病毒感染者中持续存在这种激活的后果包括认知障碍，心血管疾病和代谢异常。反应对于保持健康很重要，持续激活可能会不健康。我们的工作集中于 HIV 感染中的单核细胞激活以及作为以及慢性免疫激活的后果，包括损伤和干扰素α（IFNα）和脂多糖（LPS）的下游细胞效应。 HIV感染激活单核细胞释放外泌体，外泌体是膜结合的含有功能蛋白、mRNA 和丰富的小非编码的纳米颗粒这些外泌体单独可以进入并影响受体细胞。表征了活化单核细胞的外泌体并鉴定了 miR 影响与 HIV 感染相关的免疫激活我们的总体假设是携带特定 antagomiR 的靶向外泌体将减少外周激活，可能通过沉默激活的单核细胞来减少艾滋病毒感染。工程外泌体靶向 CD16+ 单核细胞并含有 antagomiR 来沉默与几个 miR 相关的激活，导致下游大脑和我们将利用功能性体外测定来确认。一旦我们鉴定出能够有效抑制炎症的antagomirs。我们将在人源化 HIV 小鼠模型中使用这些靶向外泌体评估体内反应。