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: 10343825
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343825
• 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; Macaca; Macaca mulatta; Measures; Mediator of activation protein; Methods; MicroRNAs; Modeling; Monitor; Monkeys; Pathogenesis; Patients; Peripheral; Persons; Positioning Attribute; Positron-Emission Tomography; Primates; Process; Production; 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; 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.

项目总结摘要 艾滋病毒感染会导致心血管/肺部并发症，75%以上的慢性艾滋病毒患者 出现临床症状的疾病，即使长期成功地联合抗逆转录病毒治疗也是如此 (购物车)。内皮细胞功能障碍是HIV相关心肺并发症的核心。受到威胁 内皮细胞导致白细胞迁移增加，HIV感染，并建立高度 炎性环境，进一步加重艾滋病毒相关的心肺疾病，包括加速- 明显的老化或“发炎”。几乎每种类型的细胞都会分泌胞外小泡。许多类型的 胞外囊泡的存在，我们将统称为EVS。它们被释放到循环中， 影响来自其蜂窝源的本地和远程站点的细胞间通信。因此，肺 内皮细胞和下面的实质不断地暴露在EVS中。感染SIV或HIV可能 影响肠道病毒的组成，促进病毒的发病和传播。来自高效感染细胞的EV 外围储存部位，包括淋巴结和胃肠道，可能含有病毒蛋白、宿主microRNAs和 在心脏和肺中触发反应的蛋白质，所有这些都可以促进炎症。我们的合作团队- 演讲者展示了在HIV相关癌症患者和动物模型中循环的EV，以及在无毒症患者中循环的EV 人类病人。有理由认为，含有病毒蛋白的EV，包括Nef，可能有助于 与艾滋病毒相关的心肺并发症。已有多项研究表明，这些蛋白质在体内起作用。 通过上调黏附分子，从而触发内皮细胞功能的明显变化。 细胞因子的分泌和caspase3的激活。然而，EV的产生、组成和功能，特别是 在CART成功抑制SIV感染的背景下，这代表了我们知识的一个重大缺口。 因此，迫切需要了解EVS在SIV相关性心肺疾病发病机制中的作用。 以及CART如何影响SIV EV诱导的细胞间通讯。这个R01应用程序，它 搭乘NIH资助的几个项目，寻求解决长期成功的CART如何影响电动汽车 货物以及来自SIV感染细胞的EV如何引起炎症，重点是内皮细胞功能障碍。