Exploratory Research on HIV Contribution to Heart and Lung Comorbidities

HIV 对心肺合并症影响的探索性研究

• 批准号: 10569641
• 负责人: ANDREW G MACLEAN
• 金额: $ 58.55万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569641
• 关键词: AIDS related cancer; Acceleration; Acute; Address; Affect; Aging; Animal Model; Animals; Apoptosis; Autopsy; Biochemistry; Biological; Biological Assay; Blood; Body Fluids; Bronchoalveolar Lavage; CASP3 gene; Cancer Patient; Cardiopulmonary; Cardiovascular system; Cell Adhesion Molecules; Cell Communication; Cell physiology; Cells; Cellular Morphology; Cellular biology; Chronic; Circulation; Clinical; Collaborations; Color; Data; Disease; Distant; Endothelial Cells; Endothelium; Exposure to; Flow Cytometry; Functional disorder; Funding; Gastrointestinal tract structure; HIV; HIV Infections; HIV/AIDS; Heart; Human; Immunohistochemistry; Indiana; Infection; Inflammaging; Infusion procedures; Intercellular Communication Induction; Knowledge; Label; Leukocytes; Link; Liposomes; Liquid substance; Lung; Macaca; Macaca mulatta; Macrophage; Measures; Mediator; Methods; MicroRNAs; Modeling; Monitor; Monkeys; PET/CT scan; Pathogenesis; Patients; Peripheral; Persons; Positioning Attribute; Primates; Process; Production; Productivity; Proteins; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Inflammation; RNA; Research; Resources; Risk; Role; SIV; Sampling; Site; Sleep; Source; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; United States National Institutes of Health; Universities; Up-Regulation; Vesicle; Viral; Viral Pathogenesis; Viral Proteins; Work; X-Ray Computed Tomography; antiretroviral therapy; automated analysis; cell behavior; cell type; communication device; comorbidity; cytokine; endothelial dysfunction; exosome; experience; extracellular; extracellular vesicles; humanized mouse; in vivo; inflammatory milieu; intercellular communication; lymph nodes; medical schools; microvesicles; migration; mouse model; nef Protein; novel; particle; premature; protein profiling; pulmonary function; response; senescence; tool

PROJECT SUMMARY ABSTRACT HIV infection results in cardiovascular/ pulmonary complications, with over 75% of patients with chronic HIV disease showing clinical manifestations, even when on long-term successful combination antiretroviral therapy (cART). Endothelial cell dysfunction is central to HIV-associated cardiopulmonary complications. Compromised endothelial cells result in increased leukocyte transmigration, HIV infection, and the establishment of a highly inflammatory environment, which further aggravates HIV-associated cardiopulmonary disease, including accel- erated aging or “inflammaging”. Extracellular vesicles are secreted from nearly every cell type. Many types of extracellular vesicle exist, which we shall refer to collectively as EVs. They are released into the circulation, influencing intercellular communication at both local and distant sites from their cellular source. Thus, pulmonary endothelial cells, and the underlying parenchyma are constantly exposed to EVs. Infection with SIV or HIV can affect the composition of EVs, facilitating viral pathogenesis and spread. EVs from productively-infected cells in peripheral reservoir sites, including lymph nodes and GI tract, can contain viral proteins, host microRNAs and proteins that trigger responses in the heart and lung, all of which can promote inflammaging. Our team of collab- orators showed this for EVs circulating in HIV-associated cancer patients and animal models, and in aviremic human patients. It is reasonable to assume that EVs containing viral proteins, including Nef, could contribute to HIV-associated cardiopulmonary complications. Several studies have demonstrated that these proteins inde- pendently trigger distinct changes in endothelial cell function through upregulation of adhesion molecules, se- cretion of cytokines and activation of caspase 3. However, EV production, composition and function, especially in the context of successful cART suppression of SIV infection, represents a significant gap in our knowledge. Therefore, there is a critical need to understand the role of EVs in pathogenesis of SIV-associated cardiopulmo- nary disease and how cART influences SIV EV-induced intercellular communication. This R01 application, which piggy-backs on several NIH-funded projects, seeks to address how long-term successful cART influences EV cargo and how EV from SIV-infected cells induce inflammaging, focusing on endothelial cell dysfunction.

项目摘要摘要 HIV感染会导致心血管/肺部汇编，其中超过75％的慢性HIB患者 疾病表现出临床表现，即使在长期成功的组合抗逆转 （购物车）。 内皮细胞导致白细胞传播，HIV感染增加，并建立高度 炎症环境进一步加剧了与HIV相关的心肺疾病，包括加速 衰老或“炎症” 存在细胞外囊泡，我们将其称为EV。 影响局部和远处的细胞间通信 内皮细胞和潜在的实质暴露于SIV或HIB感染。 影响电动汽车的组成，促进病毒发病机理和扩散。 外围储层位点，含淋巴结和胃肠道，含有病毒蛋白，宿主microRNA和 触发心脏和肺部反应的蛋白质，所有这些都会促进我们的炎症。 演说家展示了这一点用于在与HIV相关的取消癌症患者和动物模型中循环 人类患者。 与HIV相关的心肺并发症。 通过上调粘附分子，se-的上调，被触发了触发希瑟氏细胞细胞功能的明显变化 细胞因子和caspase 3的激活3。但是，EV的产生，组成和功能，尤其是 在成功推动SIV感染的推车的背景下，我们的知识上有很大的差距。 因此，批判性需要了解EV中的作用 Nary病以及购物车如何影响SIV EV诱导的细胞间通信。 关于严重性NIH资助的项目的背包，试图解决长期成功的购物车如何影响EV 货物以及来自SIV感染细胞的EV诱导炎症，重点是内皮细胞细胞细胞功能障碍。