Extracellular Vesicle-Mediated Immunomodulation in HIV Infection and Nicotine Abuse

HIV 感染和尼古丁滥用中细胞外囊泡介导的免疫调节

基本信息

批准号：
9086347
负责人：
Kenneth W Witwer
金额：
$ 46.33万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086347
关键词：
Accounting Acquired Immunodeficiency Syndrome Acute Address Affect Anti-HIV Agents Antigens Area B-Lymphocytes Biogenesis Bioinformatics Biological Assay Bone Diseases CD4 Positive T Lymphocytes CD8B1 gene Cardiovascular system Cell Line Cell membrane Cell physiology Cells Cessation of life Characteristics Cigarette Clinical Communication Cytosol Development Diagnosis Disease Epidemic Exposure to General Population Goals HIV HIV Infections HIV-1 Health Immune Immune System Diseases Immune response Immune system Immunology Individual Infection Inflammation Inflammatory International Intracellular Membranes Investigation Kidney Diseases Life Lipid Bilayers Lipids Malignant Neoplasms Mediating Medicine Membrane Methods Modification Molecular Morbidity - disease rate Neurologic Nicotine Nucleic Acids Pathogenesis Pathway interactions Patients Persons Plasma Play Population Process Property Proteins Proteomics RNA Research Research Personnel Role SNAP receptor Sampling Signal Transduction Site Smoker Smoking Structure Substance abuse problem T-Lymphocyte Techniques Therapeutic Therapeutic Intervention Validation Virion Virus Virus Replication adaptive immunity antiretroviral therapy base cell type cigarette smoke-induced cigarette smoking cigarette smoking environmental tobacco smoke exposure exosome experience extracellular vesicles genome editing immune activation immunoregulation insight intercellular communication interest macrophage monocyte nanoparticle nicotine abuse non-smoker novel novel therapeutics particle potential biomarker prevent response vesicular release

项目摘要

DESCRIPTION (provided by applicant): Combined antiretroviral therapy (cART) has dramatically changed the HIV epidemic, prolonging life and reducing morbidities. Nevertheless, a wide range of non-AIDS conditions continue to afflict people living with HIV, including cancers as well as cardiovascular, neurologic, kidney and bone diseases. These conditions are caused or influenced by inflammation states and immune activation and dysfunction that persist despite successful cART. In some cases, these conditions may be exacerbated by substance abuse, for example, cigarette smoking, which is more prevalent amongst HIV-infected individuals than in the general population. Extracellular vesicles (EV), including "exosomes" that bud into endosomal compartments, are membrane particles release by all known cell types that engage in intercellular communication. EV contribute to disease pathogenesis and are actively investigated, especially in cancers, as biomarkers and potential therapeutic platforms. Unfortunately, there is a relative dearth of information on the role of EV in HIV infection and substance abuse. To address this need in HIV and cigarette abuse, we have assembled an outstanding international team with combined strengths in HIV, EV, and immunology research, and technical portfolios ranging from EV isolation, nanoparticle characterization, and EV functional assays to bioinformatics, proteomics, lipidomics, and RNomics. Our investigators have identified a plasma signature of acute retroviral infection; characterized the roles of cellulr proteins in exosome and HIV release; unraveled the immunomodulatory function of EV; and confirmed effects of cigarettes on the immune system. Here, we will identify cellular proteins differentially involved in HIV and EV release (Aim 1), then use these findings and other methods to characterize "omics" changes to CD4+ T cell and macrophage exosomes and EV that occur with HIV infection or exposure to components of cigarette smoke (Aim 2). Functional studies will demonstrate how CD4+ T cell and macrophage EV released in HIV infection and nicotine abuse affect the qualities and function of cells that contribute to innate and adaptive immune responses (Aim 3). Finally, quantity, compositional quality, and function of circulating EV will be assessed in smoking and nonsmoking individuals who are diagnosed with HIV, both before and after they begin cART (Aim 4). The goal of these studies is to define the role played by exosomes/EVs in the promotion of pro-inflammatory states in HIV-1 infected individuals and smokers. Our findings will provide important insights into the pathogenesis of immune dysfunction/inflammation observed in these populations. We expect that our results will open pathways to new, likely EV-based, therapeutic interventions, helping to solve one of the major clinical challenges in HIV-1 medicine: the lack of treatments to limit immune activation and inflammation in HIV+ persons treated with cART.

描述：抗逆转录病毒（CART）急剧改变了Hibe的流行，延长了寿命和降低的rbidition，但widele范围的非艾滋病系列包含与HIV生活的非辅助药物. THE CONDITIONS ARE CAUSEDED BY INFLAMMATION STATES and IMMUNE AND DYSFUNCTION THAT PERS IST DESPITE SUCCESSSFUL CASES, THESE CONDITIONS MAY BE EXACERBATED by Substance Abuse, for Example, Cigarette Smoking, Which is More Prevalent Amongsted INDIVIDUALS THAN IN THE GENERALAL POPULATION. OMAL COMPARTMENTS, ALTICLES通过在生物标志物和潜在的治疗平台中，通过释放所有已知的细胞类型。，我们在HIB方面拥有一支杰出的国际团队，以及对生物信息学，蛋白质组学，脂质组学和RNOMICS的EV功能测定法，并确定了我们的研究人员的急性逆转录病毒感染。外部和艾滋病毒释放中的蛋白质；烟雾（AIM 2）将证明CD4+ T细胞和巨噬细胞EV在HIV感染和尼古丁滥用中释放以及细胞的功能有助于先天和适应性免疫反应（最后3） EV会在开始购物车之前和之后，在吸烟和非吸烟的人中被诊断出患有艾滋病毒（AIM 4）期望我们的结果将开辟新的，可能是基于EV的基于EV的治疗干预措施，有助于解决HIV-1医学中的主要临床挑战：缺乏用于用购物车治疗的HIV+人的Limmune激活和炎症的治疗方法。