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：
10664903
负责人：
Matthias Clauss
金额：
$ 58.88万
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 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664903
关键词：
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 Encapsulated Endothelial Cells Endothelium Flow Cytometry Future HIV HIV Seropositivity HIV therapy HIV/AIDS Health Heart Homing Human immunodeficiency virus test In Vitro Incubated Inflammaging Inflammation Inflammatory Integrins Intervention Label Laboratories Lead Link Liquid substance Location Lung Lung diseases Mass Spectrum Analysis Membrane Proteins Mus Pathology Patients Persons Phenotype Plasma Plasmids Population Premature aging syndrome Printing 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 Transfection 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 comorbidity early onset endothelial stem cell extracellular vesicles foot imaging software in vivo in vivo Model inhibitor 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.

项目摘要由于有效的抗逆转录病毒疗法（ART），其病毒负荷低于目标水平的HIV感染者在慢性HIV患者中，继续存在心肺疾病的风险增加疾病显示临床表现。申请人实验室的最新研究提供了证据 HIV蛋白，尤其是HIV-NEF保留在HIV患者的血浆和肺液中抗逆转录病毒疗法（ART）。基于此前的工作，我们计划在体外阐明并在体内对内皮损伤和过早衰老的机制进行建模。我们的主要假设是细胞内HIV蛋白与HIV-NEF一起从细胞中释放，并通过细胞外蔬菜传播（EV）引起心肺变化，导致合并症。在AIM 1中，我们将研究HIV蛋白细胞外蔬菜及其与特定的货物的关联，重点是表面和周内方向。检测特定EV相关的HIV蛋白的表面标记将允许将来治疗和诊断应用，包括基于抗体的靶向技术。在AIM 2中，我们将分析与EV相关的HIV蛋白在将HIV与与HIV与HIV相关的货物遍布到人体中的作用提高炎症和细胞感应。特别是，我们将使用多抗体面板来确定细胞 “归属” EV的身份和位置。在AIM 3中，我们将重点关注递送的HIV-EV的病理相关的货物。作为本金的证明，我们将测试包括ADAM17在内的特定干预策略临床前小鼠模型中的抑制剂和鼻溶剂通过EV递送HIV蛋白。