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

基本信息

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
项目类别：
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

项目摘要

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）已成为HIV-1感染患者的主要死亡原因。将HIV-1感染，CVD和与HIV感染相关的免疫系统激活（免疫激活）连接的机制尚不清楚。高密度脂蛋白（HDL）在调节炎症和免疫力中具有关键作用。 HDL通常具有针对氧化脂质和CVD的保护作用，并且具有正常的有效抗氧化作用。但是，HDL在体内进行连续重塑，在系统性炎症期间，它可以被氧化，失去其正常的抗氧化剂功能，并变得功能失调且促氧化剂。我们最近表明，HIV-1感染的受试者具有功能失调的HDL，它增加了单核细胞趋化性，这是动脉粥样硬化中的关键事件，体外，这也与HIV感染受试者的动脉粥样硬化和动脉粥样硬化的生物标志物显着相关。因此，一项评估功能失调的HDL作为可能的机理联系的研究，以及HIV-1感染中免疫激活率和CVD增加的新贡献者是该患者人群的一种新方法。该奖项申请旨在通过指导，免疫学，病毒学，脂肪学和生物统计学方面的指导，正规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以解释HIV感染中CVD的增加。为了检验这一假设，我们将确定介导氧化的HDL和细胞之间对HIV诱导的免疫激活和动脉粥样硬化很重要的细胞之间的串扰的机制（AIM 1）。先前发表的数据表明，HDL可能具有抗病毒活性，并且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AIM 2中，我们将研究氧化的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，并增加驱动免疫激活和炎症的病毒血症。最后，在我们的初步发现的指导下，可以模仿正常HDL（HDL模拟）功能的药物可以在HIV-1感染受试者的体外改善HDL功能，我们将研究在体外施用HDL模拟物，是否可以减少HIV诱导的免疫激活和HIV-1-1 Intectitive（HIV诱导）是否可以降低HIV诱导的受试者。拟议的研究中要生成的数据将允许确定氧化的HDL是否是HIV-1，免疫激活和动脉粥样硬化之间的新机械联系。这项研究的长期目标是为进一步研究的基础奠定基础，该研究是否可以在HIV感染中使用HDL Mimetics。相关性：与普通人群相比，接受抗病毒治疗的HIV感染患者过早地死于心血管疾病（CVD），但是将HIV感染，CVD和免疫系统激活（免疫激活）联系起来的机制仍然未知。该研究建议旨在研究在HIV感染中观察到的全身性炎症期间产生的异常脂蛋白是否可以介导HIV，免疫系统和CVD之间的串扰。我们预计这项为期5年的研究将提高我们对与HIV相关的免疫激活和CVD发病机理的理解，这些发现可能会引发进一步的研究，以探索新型治疗干预措施的疗效，从而改善了HIV感染患者的预后。