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Potential Role of Extracellular Vesicles for the Development of HIV Comorbidities

细胞外囊泡在 HIV 合并症发展中的潜在作用

基本信息

批准号：
10226350
负责人：
Matthias Clauss
金额：
$ 61.97万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226350
关键词：
AIDS/HIV problem Address Aging Antibodies Antigens Biodistribution Blood Brain Cardiopulmonary Cardiovascular Diseases Cell Aging Cell Line Cells Chronic Clinical Complementary DNA Core Protein Coupled Detection Development Diagnostic Disease Endothelial Cells Flow Cytometry Future HIV HIV Seropositivity HIV therapy Health Heart Home Homing Human immunodeficiency virus test In Vitro Inflammaging Inflammation Inflammatory Integrins Intervention Label Laboratories Lead Link Liquid substance Location Lung Lung diseases Membrane Proteins Mus Pathology Patients Phenotype Plasma Plasmids Population Premature aging syndrome Proteins Pulmonary Heart Disease Research Risk Role Sleep Stains Stress Structure of parenchyma of lung Surface System T-Lymphocyte Techniques Technology Testing Therapeutic Therapeutic Intervention Tissues Travel United States National Institutes of Health Vascular Diseases Viral Viral Load result Viral reservoir Virus Virus Replication Western Blotting Work age related antiretroviral therapy base comorbidity early onset endothelial stem cell extracellular vesicles foot imaging software in vivo in vivo Model inhibitor/antagonist link protein lymph nodes magnetic beads meetings monocyte mouse model neutralizing antibody novel pre-clinical premature response senescence side effect tandem mass spectrometry

项目摘要

Project Summary HIV-infected people whose viral load is below target levels due to effective anti-retroviral therapy (ART) continue to be at increased risk for cardio-pulmonary disease with over 75% of patients with chronic HIV disease showing clinical manifestations. Recent studies in the laboratories of the applicants provided evidence that HIV proteins and in particular HIV-Nef is retained in plasma and lung fluids of HIV patients on effective combined anti-retroviral therapy (ART). Based on this previous work we plan to elucidate in preclinical in vitro and in vivo models the mechanism of endothelia damage and premature aging. Our main hypothesis is that intracellular HIV proteins are released from cells together with HIV-Nef and travel through extracellular vesicles (EV) to cause cardiopulmonary changes leading to comorbidities. In aim 1 we will study HIV-proteins in extracellular vesicles and their association with specific cargo with focus on surface- and intra-vesicular orientation. The detection of surface markers for specific EV-associated HIV proteins, will allow for future therapeutic and diagnostic applications including antibody-based targeting techniques. In aim 2, we will analyze the role EV-associated HIV proteins in delivering HIV-EV-associated cargo throughout the body to increase inflammation and cell senescence. Specifically, we will use multi-antibody panels to determine cell identity and location of the “homed” EV. In aim 3, we will focus on the pathology of the delivered HIV-EV associated cargo. As a proof of principal we will test specific intervention strategies including ADAM17 inhibitors and senolytic agents in preclinical mouse models for HIV-protein delivery through EV.

项目摘要因有效的抗逆转录病毒治疗(ART)病毒载量低于目标水平的艾滋病毒感染者 75%以上的慢性艾滋病毒携带者患心肺疾病的风险继续增加表现为临床症状的疾病。申请者实验室最近的研究提供了证据 HIV蛋白，特别是HIV-Nef被有效地保留在HIV患者的血浆和肺液中联合抗逆转录病毒疗法(ART)。基于这项先前的工作，我们计划在体外阐明临床前并在体内模拟血管内皮损伤和过早衰老的机制。我们的主要假设是细胞内的HIV蛋白与HIV-Nef一起从细胞中释放出来，并通过细胞外的小泡运输 (EV)引起心肺变化，导致合并症。在目标1中，我们将研究HIV-蛋白质细胞外小泡及其与特定货物的关系，主要集中在表面和内小泡上定位。对特定EV相关HIV蛋白表面标记的检测将允许未来治疗和诊断应用，包括基于抗体的靶向技术。在目标2中，我们将分析EV相关HIV蛋白在将HIV-EV相关货物运送到全身的过程中所起的作用增加炎症和细胞衰老。具体地说，我们将使用多个抗体小组来确定细胞 “归宿”电动汽车的身份和位置。在目标3中，我们将重点介绍交付的艾滋病毒-EV的病理相关货物。作为原则的证明，我们将测试具体的干预策略，包括ADAM17 通过EV传递HIV-蛋白质的临床前小鼠模型中的抑制物和老年溶解剂。