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

• 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
• 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

 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（由申请人提供）：联合抗逆转录病毒疗法（cART）极大地改变了艾滋病毒的流行，延长了生命，降低了发病率。尽管如此，艾滋病毒感染者仍受到各种非艾滋病疾病的困扰，包括癌症以及心血管、神经、肾脏和骨骼疾病。这些病症是由炎症状态和免疫激活和功能障碍引起或影响的，尽管cART成功，但这些状态和功能障碍仍然存在。在某些情况下，这些情况可能会因药物滥用而加剧，例如吸烟，这在艾滋病毒感染者中比在一般人群中更为普遍。细胞外囊泡（EV），包括出芽进入内体区室的“外来体”，是由参与细胞间通讯的所有已知细胞类型释放的膜颗粒。EV有助于疾病的发病机制，并被积极研究，特别是在癌症中，作为生物标志物和潜在的治疗平台。不幸的是，EV在HIV感染和药物滥用中的作用的信息相对缺乏。为了满足艾滋病毒和香烟滥用的这一需求，我们组建了一支杰出的国际团队，该团队在艾滋病毒，EV和免疫学研究方面具有综合优势，技术组合包括EV分离，纳米颗粒表征和EV功能测定，生物信息学，蛋白质组学，脂质组学和RNomics。我们的研究人员已经确定了急性逆转录病毒感染的血浆特征;表征了细胞蛋白在外泌体和HIV释放中的作用;揭示了EV的免疫调节功能;并证实了香烟对免疫系统的影响。在这里，我们将确定差异参与HIV和EV释放的细胞蛋白（目标1），然后使用这些发现和其他方法来表征HIV感染或暴露于香烟烟雾成分时发生的CD 4 + T细胞和巨噬细胞外泌体和EV的“组学”变化（目标2）。功能研究将证明HIV感染和尼古丁滥用中释放的CD 4 + T细胞和巨噬细胞EV如何影响有助于先天性和适应性免疫应答的细胞的质量和功能（目的3）。最后，将对循环EV的数量、组成质量和功能进行分析。 在诊断为HIV的吸烟和非吸烟个体中，在他们开始cART之前和之后进行评估（目标4）。 这些研究的目的是确定外泌体/EV在促进HIV-1感染者和吸烟者的促炎状态中所起的作用。我们的研究结果将为这些人群中观察到的免疫功能障碍/炎症的发病机制提供重要的见解。我们希望我们的研究结果将为新的、可能基于EV的治疗干预开辟途径，帮助解决HIV-1医学的主要临床挑战之一：缺乏限制接受cART治疗的HIV+患者免疫激活和炎症的治疗方法。