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

描述(申请人提供)：心血管疾病(CVD)正成为HIV-1感染者死亡的主要原因。将艾滋病毒-1感染、心血管疾病和与艾滋病毒感染相关的免疫系统激活(免疫激活)联系起来的机制尚不清楚。高密度脂蛋白(高密度脂蛋白)在调节炎症和免疫方面起着关键作用。高密度脂蛋白一般对氧化脂质和心血管疾病有保护作用，并具有正常的强大抗氧化作用。然而，高密度脂蛋白在体内受到持续的重塑，在全身炎症期间，它可以被氧化，失去正常的抗氧化功能，成为功能障碍和促氧化剂。我们最近发现，HIV-1感染者的高密度脂蛋白功能障碍，在体外增加了单核细胞趋化能力，这是动脉粥样硬化的关键事件，也与艾滋病毒感染者T细胞激活和动脉粥样硬化进展的生物标志物显著相关。因此，一项研究评估功能失调的高密度脂蛋白是HIV-1感染中免疫激活率和心血管疾病增加的一个可能的机制链接和新的贡献者，是在这一患者群体中的一种新的方法。此奖项申请旨在通过指导、免疫学、病毒学、血脂学和生物统计学方面的正式培训来支持申请者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、氧化型高密度脂蛋白的产生以及进一步的免疫激活的恶性循环可能解释了HIV感染中心血管疾病发生率增加的原因。为了验证这一假设，我们将确定氧化的高密度脂蛋白和对艾滋病毒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调节机制(目标1)。此前公布的数据表明，高密度脂蛋白可能具有抗病毒活性，氧化的脂类可能直接调节免疫并影响艾滋病毒的传染性。鉴于这些数据，在目标2中，我们将调查氧化的高密度脂蛋白是否直接影响HIV-1的生命周期，并导致细胞毒性CD8 T细胞的抗病毒反应降低，以及驱动免疫激活和炎症的病毒血症增加。最后，根据我们的初步发现，给予一种可以模拟正常高密度脂蛋白功能的药物(高密度脂蛋白模拟物)可以在体外改善HIV-1感染者的高密度脂蛋白功能，我们将调查体外给药高密度脂蛋白模拟物是否可以降低艾滋病毒诱导的免疫激活和艾滋病毒-1的传染性(目标1，2)。在拟议的研究中产生的数据将允许确定氧化的高密度脂蛋白是否是HIV-1、免疫激活和动脉粥样硬化之间的一种新的机制联系。这项研究的长期目标是为进一步研究高密度脂蛋白模拟物是否可以用于治疗艾滋病毒感染提供基础。 相关性：与普通人群相比，接受抗病毒治疗的艾滋病毒感染患者过早死于心血管疾病(CVD)，但将艾滋病毒感染、心血管疾病和免疫系统激活(免疫激活)联系起来的机制仍不清楚。这项研究计划旨在调查在艾滋病毒感染的全身炎症过程中产生的异常脂蛋白是否可能介导艾滋病毒、免疫系统和心血管疾病之间的串扰。我们预计，这项为期5年的研究将提高我们对HIV相关免疫激活和心血管疾病发病机制的理解，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有效性。

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.