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

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。将HIV-1感染、CVD和与HIV感染相关的免疫系统激活（免疫激活）联系起来的机制仍然未知。高密度脂蛋白（HDL）在调节炎症和免疫方面具有关键作用。HDL对氧化脂质和CVD具有普遍的保护作用，并具有正常的有效抗氧化作用。然而，HDL在体内经历持续的重塑，并且在全身性炎症期间，它可以被氧化，失去其正常的抗氧化功能，并且变得功能障碍和促氧化剂。我们最近发现，HIV-1感染的受试者具有功能失调的HDL，其增加单核细胞趋化性，这是体外动脉粥样硬化形成的关键事件，并且还与HIV感染受试者中T细胞活化和动脉粥样硬化进展的生物标志物显著相关。因此，一项研究，以评估功能障碍的HDL作为一个可能的机制联系和一个新的贡献率增加的免疫激活和心血管疾病的HIV-1感染是一种新的方法，在这个病人群体。该奖项申请旨在通过指导，免疫学，病毒学，脂质学和生物统计学的正式培训来支持申请人的临床科学家研究职业发展奖。我们推测，HIV诱导的免疫激活、炎症、氧化HDL的产生和进一步的免疫激活的恶性循环可能解释了HIV感染中CVD发生率的增加。为了验证这一假设，我们将确定介导氧化HDL和细胞之间的相互作用的机制，这些细胞对HIV诱导的免疫激活和动脉粥样硬化形成很重要（目的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，我们将研究氧化的HDL是否直接影响HIV-1的生命周期，并导致细胞毒性CD 8 T细胞的抗病毒反应降低和驱动免疫激活和炎症的病毒血症增加。最后，根据我们的初步发现，即给予能够模拟正常HDL功能的药物（HDL模拟物）可以在体外改善HIV-1感染受试者的HDL功能，我们将研究体外给予HDL模拟物是否可以降低HIV诱导的免疫激活和HIV-1感染性（目的1，2）。在拟议的研究中产生的数据将允许确定氧化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。本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：与一般人群相比，接受抗病毒治疗的HIV感染患者过早死于心血管疾病（CVD），但将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。这项研究旨在调查在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疗效。

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.