Oxidized HDL in the intersection of HIV, immune activation and atherosclerosis

HIV、免疫激活和动脉粥样硬化交叉点中的氧化 HDL

• 批准号: 8719933
• 负责人: Theodoros Kelesidis
• 金额: $ 17.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-12 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719933
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antiviral Agents; Antiviral Response; Antiviral Therapy; Atherosclerosis; Award; Biological Markers; Biometry; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Communication; Cell membrane; Cells; Cellular biology; Chemotaxis; Chronic; Clinical; Complex; Data; Development; Disease; Drug Formulations; Event; Foundations; General Population; Goals; HIV; HIV Infections; HIV-1; High Density Lipoproteins; Immune; Immune system; Immunity; Immunology; In Vitro; Infection; Inflammation; K-Series Research Career Programs; Laboratories; Life; Life Cycle Stages; Link; Lipids; Lipoproteins; Mediating; Mediator of activation protein; Mentors; Morbidity - disease rate; Pathogenesis; Patients; Peptides; Persons; Pharmaceutical Preparations; Play; Process; Production; Public Health; Publishing; Reactive Oxygen Species; Reporting; Research; Research Proposals; Role; Scientist; T-Cell Activation; T-Lymphocyte; Testing; Training; Viral; Viremia; Virus; Work; atherogenesis; cardiovascular disorder risk; cytotoxic; design; immune activation; improved; in vivo; innovation; macrophage; mimetics; monocyte; mortality; novel; novel strategies; novel therapeutic intervention; outcome forecast; oxidation; oxidized lipid; patient population; protective effect; virology

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is becoming a major cause of death in persons with HIV-1 infection. The mechanisms that link HIV-1 infection, CVD and activation of the immune system associated with HIV infection (immune activation) remain unknown. High density lipoproteins (HDL) have key roles in moderating inflammation and immunity. HDL has generally protective effects against oxidized lipids and CVD, and has a normal potent antioxidant role. However, HDL is subject to continuous remodeling in vivo and during systemic inflammation it can be oxidized, lose its normal antioxidant functions, and become dysfunctional and pro-oxidant. We have recently shown that HIV-1 infected subjects have dysfunctional HDL that increases monocyte chemotaxis, a key event in atherogenesis, in vitro and that also is significantly associated with biomarkers of T cell activation and progressio of atherosclerosis in HIV-infected subjects. Therefore, a study to assess dysfunctional HDL as a possible mechanistic link and a new contributor to the increased rate of immune activation and CVD in HIV-1 infection is a novel approach in this patient population. This award application is intended to support the applicant's clinical scientist research career development award through mentoring, formal training in immunology, virology, lipidology and biostatistics. We hypothesize that a vicious cycle of HIV-induced immune activation, inflammation, production of oxidized HDL, and further immune activation may explain the increased rate of CVD in HIV infection. To test this hypothesis, we will determine the mechanisms that mediate the cross-talk between oxidized HDL and cells important for HIV-induced immune activation and atherogenesis (Aim 1). Previously published data have demonstrated HDL may have antiviral activity and that oxidized lipids may directly modulate immunity and affect HIV infectivity. In view of these data, in Aim 2, we will investigate whether oxidized HDL directly affects the life cycle of HIV-1 and leads to reduced antiviral responses of cytotoxic CD8 T cells and increased viremia that drives immune activation and inflammation. Finally, guided by our preliminary findings that administration of a drug that can mimic the function of normal HDL (HDL mimetic) may improve HDL function in vitro in HIV-1 infected subjects, we will investigate whether in vitro administration of HDL mimetics, can reduce HIV-induced immune activation and HIV-1 infectivity (Aims 1, 2). The data to be generated in the proposed study will allow to determine whether oxidized HDL is a novel mechanistic link between HIV-1, immune activation and atherosclerosis. The long-term goals of this research are to provide the foundation for further studies whether HDL mimetics can be used therapeutically in HIV infection. RELEVANCE: HIV-infected patients receiving antiviral therapy die prematurely of cardiovascular disease (CVD), compared to the general population but the mechanisms that link HIV infection, CVD and activation of the immune system (immune activation) remain unknown. This research proposal is designed to investigate whether abnormal lipoproteins that are produced during systemic inflammation seen with HIV infection may mediate the cross-talk between HIV, the immune system and CVD. We anticipate that this 5-year study will improve our understanding of the pathogenesis of HIV-associated immune activation and CVD and these findings may initiate further studies to explore the efficacy of novel therapeutic interventions that might improve the prognosis of HIV-infected patients.

描述（由申请人提供）：心血管疾病 (CVD) 正在成为 HIV-1 感染者死亡的主要原因。 HIV-1 感染、CVD 和与 HIV 感染相关的免疫系统激活（免疫激活）之间的联系机制仍不清楚。高密度脂蛋白（HDL）在调节炎症和免疫方面发挥着关键作用。 HDL 通常具有针对氧化脂质和 CVD 的保护作用，并具有正常的有效抗氧化作用。然而，HDL 在体内会持续重塑，在全身炎症过程中，它可能会被氧化，失去正常的抗氧化功能，并变得功能失调和促氧化。我们最近发现，HIV-1 感染者的 HDL 功能失调，在体外会增加单核细胞趋化性，这是动脉粥样硬化形成的关键事件，并且与 HIV 感染者中 T 细胞活化和动脉粥样硬化进展的生物标志物显着相关。因此，一项研究评估功能失调的 HDL 作为一种可能的机制联系以及 HIV-1 感染中免疫激活和 CVD 率增加的新贡献者，是针对该患者群体的一种新方法。该奖项申请旨在通过免疫学、病毒学、脂质学和生物统计学方面的指导、正式培训来支持申请人的临床科学家研究职业发展奖。我们假设，HIV 诱导的免疫激活、炎症、氧化 HDL 的产生以及进一步的免疫激活的恶性循环可能解释了 HIV 感染中 CVD 发病率的增加。为了检验这一假设，我们将确定介导氧化 HDL 与对 HIV 诱导的免疫激活和动脉粥样硬化重要的细胞之间的串扰的机制（目标 1）。先前发表的数据表明，HDL 可能具有抗病毒活性，氧化脂质可能直接调节免疫力并影响 HIV 感染性。鉴于这些数据，在目标 2 中，我们将研究氧化 HDL 是否直接影响 HIV-1 的生命周期，并导致细胞毒性 CD8 T 细胞的抗病毒反应减少以及驱动免疫激活和炎症的病毒血症增加。最后，根据我们的初步研究结果，即给予一种可以模仿正常 HDL 功能的药物（HDL 模拟物）可能会在体外改善 HIV-1 感染受试者的 HDL 功能，我们将研究体外给予 HDL 模拟物是否可以减少HIV 诱导的免疫激活和 HIV-1 感染性（目标 1、2）。拟议研究中产生的数据将有助于确定氧化 HDL 是否是 HIV-1、免疫激活和动脉粥样硬化之间的新机制联系。这项研究的长期目标是为进一步研究 HDL 模拟物是否可用于治疗 HIV 感染提供基础。 相关性：与普通人群相比，接受抗病毒治疗的 HIV 感染患者会因心血管疾病 (CVD) 过早死亡，但 HIV 感染、CVD 和免疫系统激活（免疫激活）之间的联系机制仍不清楚。本研究计划旨在调查 HIV 感染引起的全身炎症过程中产生的异常脂蛋白是否可能介导 HIV、免疫系统和 CVD 之间的相互作用。我们预计这项为期 5 年的研究将提高我们对 HIV 相关免疫激活和 CVD 发病机制的理解，这些发现可能会启动进一步的研究，以探索可能改善 HIV 感染患者预后的新型治疗干预措施的功效。