Targeting early instigators of vascular inflammation to prevent and/or delay vascular aging in chronic treated HIV

项目总结/摘要 与衰老相关的合并症增加，如动脉粥样硬化性心血管疾病（CVD），是一种 尽管进行了有效的抗逆转录病毒治疗（ART），但仍出现了HIV-1感染的新问题。目前的治疗方法（如 他汀类药物）治疗HIV-1相关炎症、免疫激活和CVD是不够的。氧化应激具有 抗氧化剂在HIV-1发病机制和CVD中起主要作用，但单独使用抗氧化剂不太可能是足够的治疗方法。 强效抗氧化剂，对多效炎症介质也有特异性抗炎作用 氧化脂质（OxPL）可能是改善HIV-1相关炎症、免疫 活化和CVD。揭示氧化脂质如何影响CVD和HIV-1发病机制，可能有助于 开发新的治疗方法来管理HIV相关的CVD。高密度脂蛋白（HDL）是最常见的 在所有大型流行病学研究中，CVD是一个强有力的独立阴性预测因子。载脂蛋白A-I 载脂蛋白A-I（apoA-I）是高密度脂蛋白的主要蛋白质， HDL的特性这些作用可以通过apoA-I肽如4F来模拟，这是有希望的治疗方法 对于CVD。他汀类药物和ApoA-I具有相似的抗炎特性。来自动物研究的证据有限 已经表明，当给予apoA-I肽时， 他汀类药物apoA-I模拟物和他汀类药物之间的协同作用可能部分地在肠道水平，这可能是肠道的一个重要方面。 动脉粥样硬化的重要调节剂。单核细胞/巨噬细胞（M/M）位于 HIV-1免疫发病机制，肠道生物学，动脉粥样硬化。鉴于HIV-1相关的复杂发病机制， 在CVD中，不可能研究他汀类药物和apoA-I模拟物之间协同作用的确切机制， 人（体内）。在加州大学洛杉矶分校内建立的患者队列和原代人类细胞和脂蛋白可以是 用作研究他汀和apoA-I模拟物的离体/体外协同作用的工具。在本建议中，使用 建立了生理学上有意义的动脉粥样硬化离体模型，我们将探索 他汀类药物和ApoA-I模拟物对确定氧化脂蛋白如何存在于慢性炎症中的机制的影响 治疗的HIV-1感染直接促进M/M衍生的泡沫细胞形成和M/M趋化性（Aim 1）， M/M功能障碍（目标2）和内皮活化（目标3）。我们还将扩大我们的研究结果在体内（目标3）， 中年/老年人（50-70岁）HIV阳性者接受有效ART和亚临床动脉粥样硬化。在这个群体中， 我们将探讨与年龄匹配的ART组相比，未使用他汀类药物的受试者是否有 较低的血浆氧化脂蛋白水平和确定的替代生物标志物和分子特征， M/M和内皮激活，已知预测和/或导致CVD。这种方法可以减少 尽管在HIV-1感染的老年人中进行了抗逆转录病毒治疗，但发病率和死亡率仍然过高。这项工作是 创新，对公共卫生有潜在的影响，并直接解决有关老龄化的研究重点， 慢性HIV

PROJECT SUMMARY/ABSTRACT Increased comorbidities associated with aging such as atherosclerotic cardiovascular disease (CVD) is an emerging problem in HIV-1 infection despite potent antiretroviral therapy (ART). Current therapies (such as statins) to treat HIV-1-related inflammation, immune activation and CVD are inadequate. Oxidative stress has a major role in HIV-1 pathogenesis and CVD but it is unlikely that antioxidants alone will be adequate therapy. Potent antioxidants that also have specific anti-inflammatory effects against pleotropic inflammatory mediators called oxidized lipids (OxPLs) may be novel therapies to improve HIV-1 related inflammation, immune activation and CVD. Unraveling how oxidized lipids affect CVD and HIV-1 pathogenesis, may contribute to development of new therapies to manage HIV-related CVD. High-density lipoproteins (HDLs) are the most powerful independent negative predictor of CVD evident in all large epidemiological studies. Apolipoprotein A-I (apoA-I), the major protein of HDL, is responsible for the much of the anti-atherogenic and anti-inflammatory properties of HDL. These effects can be mimicked by apoA-I peptides such as 4F that are promising therapy for CVD. Statins and ApoA-I have similar anti-inflammatory properties. Limited evidence from animal studies has shown that there was enhancement of the biological properties of apoA-I peptides when given with a statin. Synergy between apoA-I mimetics and statins may in part be at the level of the intestine which may be an important modulator of atherosclerosis. Monocytes/macrophages (M/M) are at the intersection between HIV-1 immunopathogenesis, gut biology, atherosclerosis. Given the complex pathogenesis of HIV-1 related CVD, it is impossible to study exact mechanisms of synergistic effects between statins and apoA-I mimetics in humans (in vivo). Established patient cohorts within UCLA and primary human cells and lipoproteins can be used as tools to study ex vivo/in vitro synergistic effects of statin and apoA-I mimetics. In this proposal using an established physiologically meaningful ex vivo model of atherosclerosis we will explore synergistic effects of statins and ApoA-I mimetics on mechanisms that determine how oxidized lipoproteins present in chronic treated HIV-1 infection directly contribute to M/M derived foam cell formation and M/M chemotaxis (Aim 1), M/M dysfunction (Aims 2) and endothelial activation (Aim 3). We will also expand our findings in vivo (Aim 3) in middle aged/older (50-70 years old) HIV+ persons on potent ART and subclinical atherosclerosis. In this group, we will explore whether compared to matched by age, ART group not on statins, participants on statins have lower plasma levels of oxidized lipoproteins and established surrogate biomarkers and molecular signatures of M/M and endothelial activation that are known to predict and/or lead to CVD. Such an approach could reduce the excess morbidity and mortality remaining despite ART in HIV-1 infected aged persons. This work is innovative, has a potential impact on public health and directly addresses research priorities regarding aging in chronic HIV.