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: 10012373
• 负责人: ANDREW G MACLEAN
• 金额: $ 63.2万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012373
• 关键词: AIDS related cancer; AIDS/HIV problem; Acute; Address; Affect; Aging; Animal Model; Animals; Apoptosis; Autopsy; Back; Biochemistry; Biological; Biological Assay; Blood; Blood Circulation; Body Fluids; Bronchoalveolar Lavage; CASP3 gene; Cancer Patient; Cardiopulmonary; Cardiovascular system; Cell Adhesion Molecules; Cell Communication; Cell physiology; Cells; Cellular Morphology; Cellular biology; Chronic; Clinical; Collaborations; Cytokine Activation; Data; Disease; Distant; Endothelial Cells; Endothelium; Exposure to; Flow Cytometry; Functional disorder; Funding; Gastrointestinal tract structure; HIV; HIV Infections; Heart; Human; Immunohistochemistry; Indiana; Infection; Inflammaging; Infusion procedures; Knowledge; Label; Leukocytes; Link; Liposomes; Liquid substance; Lung; Lung Inflammation; Macaca; Macaca mulatta; Measures; Mediator of activation protein; Methods; MicroRNAs; Modeling; Monitor; Monkeys; Pathogenesis; Patients; Peripheral; Positioning Attribute; Positron-Emission Tomography; Primates; Process; Production; Proteins; Pulmonary Heart Disease; Pulmonary Hypertension; 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; endothelial dysfunction; exosome; experience; extracellular; extracellular vesicles; humanized mouse; in vivo; inflammatory milieu; intercellular communication; lymph nodes; macrophage; medical schools; microvesicles; 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 艾滋病毒感染导致心血管/肺部并发症，超过75%的慢性艾滋病毒患者 疾病表现出临床表现，即使在长期成功的抗逆转录病毒联合治疗 （cART）。内皮细胞功能障碍是HIV相关心肺并发症的核心。损害 内皮细胞导致白细胞迁移增加、艾滋病毒感染以及高度依赖性的建立。 炎症环境，这进一步加剧了艾滋病毒相关的心肺疾病，包括加速， 老化或“炎症”。细胞外囊泡几乎由每种细胞类型分泌。许多类型的 存在细胞外囊泡，我们将其统称为EV。它们被释放到血液循环中， 影响来自其细胞源的本地和远端位点的细胞间通讯。因此，肺 内皮细胞和下面的实质不断地暴露于EV。SIV或HIV感染可 影响电动汽车的组成，促进病毒的发病和传播。来自生产性感染细胞的EV， 外周储库部位，包括淋巴结和胃肠道，可含有病毒蛋白、宿主microRNA和 触发心脏和肺反应的蛋白质，所有这些都可以促进炎症。我们的合作团队- 在HIV相关癌症患者和动物模型中，以及在病毒血症患者中， 人类病人有理由认为，含有病毒蛋白（包括Nef）的EV可能有助于 HIV相关的心肺并发症。一些研究表明，这些蛋白质inde- 通过上调粘附分子，间接触发内皮细胞功能的明显变化， 细胞因子的分泌和半胱天冬酶3的活化。然而，电动汽车的生产、组成和功能，特别是 在成功的cART抑制SIV感染的背景下，代表了我们知识上的一个重大空白。 因此，迫切需要了解EV在SIV相关心肺功能衰竭发病机制中的作用。 以及cART如何影响SIV EV诱导的细胞间通讯。这个R 01应用程序， 在几个NIH资助的项目上，寻求解决长期成功的cART如何影响EV 货物和EV如何从SIV感染的细胞诱导炎症，重点是内皮细胞功能障碍。