HIV-Nef protein and endothelial dysfunction

HIV-Nef 蛋白与内皮功能障碍

• 批准号: 8984518
• 负责人: Matthias Clauss
• 金额: $ 45.61万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984518
• 关键词: Acquired Immunodeficiency Syndrome; Actins; Address; Adverse effects; Aging; Anti-Retroviral Agents; Antibodies; Antioxidants; Antiviral Therapy; Apolipoprotein E; Apoptosis; Atherosclerosis; Biology; Blood Cells; Blood Vessels; Blood flow; Breeding; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell Line; Cells; Clinical; Clinical Research; Coronary; Coronary artery; Data; Disease; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Event; Fibrinogen; Functional disorder; Generations; Goals; HIV; HIV Core Protein p24; HIV Infections; HIV Seropositivity; Heart; Human; In Vitro; Individual; Intervention; Kidney; Lead; Link; Liquid substance; Lymph; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; NADP; NADPH Oxidase; Nanotubes; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Population; Pre-Clinical Model; Process; Production; Proteins; Publishing; RNA; Reactive Oxygen Species; Risk Factors; Role; SH3 Domains; Signal Transduction; Structure; System; T-Lymphocyte; Testing; Time; Transfer Factor; Transgenic Mice; Ursidae Family; Validation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Viral; Viremia; Virus; Work; base; disorder risk; endothelial dysfunction; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; intravital microscopy; mitochondrial dysfunction; mortality; novel; polymerization; pre-clinical; prevent; promoter; public health relevance; tissue culture; tissue fixing

 DESCRIPTION (provided by applicant): Antiviral therapy is effective in preventing AIDS in HIV-infected people. However, an increasing number of HIV infected individuals suffer or even die of diseases other than AIDS including cardiovascular diseases. The biology behind these clinical observations is not well understood, although both anti-retroviral therapy (ART) dependent and independent mechanisms appear to be involved. Here we plan to study a key mechanism by which HIV can cause endothelial activation and dysfunction, which are believed to precede atherosclerotic processes. Nef is known to play a pivotal role in HIV pathogenesis and to mediate its own transfer from T cells to bystander cells. Therefore, we postulate that HIV-Nef can efficiently be transferred from T cells to other blood cells including vascular endothelial cells, which are in steady contact with flowing blood and lymph fluid. Indeed, we can show that transfer of Nef leads to endothelial cell activation and cell death, which can be effectively abrogated by NADPH oxidase inhibitors and antioxidants. Based on our published data that HIV dependent endothelial activation can be explained by transfer of Nef from blood cells to coronary arterial endothelial cells, we further hypothesize that transfer of Nef to vascular cells may lead to cardiovascular dysfunction and pathology of the cardiovascular system. We plan to address in preclinical in vitro and in vivo models the mechanism of Nef transfer to and activity in endothelial cells. We expect that identifying such targets will enable clinical interventions studis with appropriate inhibitors. Thus, determining the cellular mechanism of Nef-induced vascular pathology in vascular endothelial cells can help to identify HIV-Nef as a novel target for preventing and treating HIV- associated diseases.

 描述（由申请人提供）：抗病毒治疗可有效预防艾滋病毒感染者的艾滋病。然而，越来越多的艾滋病毒感染者患有甚至死于艾滋病以外的疾病，包括心血管疾病。尽管抗逆转录病毒治疗（ART）依赖和独立机制似乎都参与其中，但这些临床观察背后的生物学原理尚不清楚。在这里，我们计划研究艾滋病毒引起内皮激活和功能障碍的关键机制，这些激活和功能被认为先于动脉粥样硬化过程。 Nef 已知在 HIV 发病机制中发挥着关键作用，并介导其自身从 T 细胞到旁观者细胞的转移。因此，我们假设 HIV-Nef 可以有效地从 T 细胞转移到其他血细胞，包括血管内皮细胞 细胞，与流动的血液和淋巴液稳定接触。事实上，我们可以证明 Nef 的转移会导致内皮细胞活化和细胞死亡，而 NADPH 氧化酶抑制剂和抗氧化剂可以有效消除这种现象。根据我们发表的数据，HIV依赖性内皮激活可以通过Nef从血细胞转移到冠状动脉内皮细胞来解释，我们进一步假设Nef转移到血管细胞可能导致心血管功能障碍和心血管系统病理。我们计划在临床前体外和体内模型中研究 Nef 转移的机制及其活性 内皮细胞。我们预计，确定这些目标将使能够使用适当的抑制剂进行临床干预研究。因此，确定血管内皮细胞中 Nef 诱导的血管病理学的细胞机制有助于将 HIV-Nef 确定为预防和治疗 HIV 相关疾病的新靶点。