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.

项目概要摘要 HIV 感染会导致心血管/肺部并发症，超过 75% 的患者患有慢性 HIV 即使进行长期成功的联合抗逆转录病毒治疗，疾病也会出现临床表现 (cART)。内皮细胞功能障碍是 HIV 相关心肺并发症的核心。 内皮细胞导致白细胞高度迁移、HIV 感染以及建立 炎症环境，进一步加剧与艾滋病毒相关的心肺疾病，包括加速 几乎所有类型的细胞都会分泌细胞外囊泡。 存在细胞外囊泡，我们将其统称为 EV，它们被释放到循环中， 细胞间通讯在局部影响和远离细胞源的部位。 内皮细胞和下面的实质持续暴露于 EV 或 HIV 感染。 影响 EV 的组成，促进病毒在有效感染细胞中的发病和传播。 外周储存部位，包括淋巴结和胃肠道，可能含有病毒蛋白、宿主 microRNA 和 触发心脏和肺部反应的蛋白质，所有这些都会促进炎症。 演说家在 HIV 相关癌症患者和动物模型以及无病毒血症中循环的 EV 中证明了这一点 可以合理地假设含有病毒蛋白（包括 Nef）的 EV 可能有助于 多项研究表明，这些蛋白质确实与 HIV 相关的心肺并发症有关。 通过上调粘附分子，se- 悬而未决地触发内皮细胞功能的明显变化 细胞因子的产生和 caspase 3 的激活。然而，EV 的产生、组成和功能，尤其是 在成功抑制 SIV 感染的 cART 的背景下，我们的知识存在重大差距。 因此，迫切需要了解 EV 在 SIV 相关心肺疾病发病机制中的作用。 疾病以及 cART 如何影响 SIV EV 诱导的细胞间通讯。此 R01 应用程序。 借助 NIH 资助的多个项目，寻求解决长期成功的 cART 如何影响 EV 货物以及来自 SIV 感染细胞的 EV 如何诱导炎症，重点关注内皮细胞功能障碍。