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

针对血管炎症的早期诱发因素，预防和/或延缓长期治疗的艾滋病毒患者的血管老化

• 批准号: 9789142
• 负责人: Theodoros Kelesidis
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789142
• 关键词: AIDS/HIV problem; Address; Affect; Age; Aging; Animals; Anti-inflammatory; Antiatherogenic; Antiinflammatory Effect; Antioxidants; Apolipoprotein A-I; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Binding; Biological; Biology; Blood Vessels; Cardiovascular Diseases; Cells; Chemotaxis; Chronic; Chronic Disease; Comorbidity; Complement; Complex; Development; Diet; Disease; Endothelial Cells; Endothelium; Foam Cells; Fostering; Frequencies; Functional disorder; Goals; HIV; HIV-1; High Density Lipoproteins; Human; Immunity; In Vitro; Infection; Inflammation; Inflammation Mediators; Intervention; Intestines; KAI1 gene; Knockout Mice; Lead; Lesion; Lipids; Lipoproteins; Mediating; Methods; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Oral Administration; Organ; Oxidative Stress; Oxides; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Physiological; Plasma; Process; Property; Proteins; Public Health; Research Priority; Research Proposals; Role; Surrogate Markers; Therapeutic; Therapeutic Agents; Tissues; Tomatoes; Transgenic Organisms; Translating; Treatment Efficacy; United States National Institutes of Health; Work; aged; antiretroviral therapy; base; cardiovascular disorder risk; cardiovascular disorder therapy; cohort; design; endothelial dysfunction; epidemiology study; experimental study; immune activation; improved; innovation; macrophage; member; microbial; middle age; mimetics; monocyte; mortality; novel; novel strategies; novel therapeutics; oxidized lipid; peptide I; peptidomimetics; peripheral blood; prevent; synergism; tool; vascular inflammation

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.

项目摘要/摘要 与衰老相关的并发症增加，如动脉粥样硬化性心血管疾病(CVD)是一种 尽管有效的抗逆转录病毒疗法(ART)，艾滋病毒-1感染仍出现问题。目前的治疗方法(例如 他汀类药物)在治疗HIV-1相关炎症、免疫激活和心血管疾病方面是不够的。氧化应激有一种 在HIV-1致病和心血管疾病中起主要作用，但单靠抗氧化剂不太可能是足够的治疗方法。 有效的抗氧化剂，对嗜多形性炎症介质也有特殊的抗炎作用 所谓的氧化脂质(Oxpls)可能是改善HIV-1相关炎症、免疫的新疗法 激活和心血管疾病。揭示氧化脂质如何影响心血管疾病和HIV-1的发病机制，可能有助于 开发新的治疗方法来管理艾滋病毒相关的心血管疾病。高密度脂蛋白(HDL)是 在所有大型流行病学研究中，心血管疾病的强大独立负预测因子都很明显。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，参与了许多抗动脉粥样硬化和抗炎的作用 高密度脂蛋白的特性。这些效应可以被apoA-I多肽(如4F)模拟，这些多肽是有希望的治疗方法 治疗心血管疾病。他汀类药物和ApoA-I具有相似的抗炎特性。来自动物研究的有限证据 研究表明，当给予载脂蛋白A-I多肽时，其生物学特性得到增强。 他汀类药物。载脂蛋白A-I模拟物和他汀类药物之间的协同作用可能部分是在肠道水平上的，这可能是 动脉粥样硬化的重要调节剂。单核/巨噬细胞(M/M)处于 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 CVD，不可能研究他汀类药物和载脂蛋白A-I模拟物之间协同作用的确切机制。 人体(活体内)。加州大学洛杉矶分校和原代人类细胞和脂蛋白中建立的患者队列 作为研究他汀类药物和载脂蛋白A-I类药物体外/体外协同作用的工具。在本提案中，使用 建立具有生理意义的动脉粥样硬化体外模型，探讨其协同作用 他汀类药物和载脂蛋白-I对决定氧化的脂蛋白在慢性粒细胞白血病中的作用机制的模拟 经治疗的艾滋病毒-1感染直接促进M/M来源泡沫细胞的形成和M/M趋化(目标1)， M/M功能障碍(AIMS 2)和内皮激活(AIMS 3)。我们还将在体内扩展我们的发现(AIM 3) 中年/老年(50-70岁)HIV+人群服用有效的抗逆转录病毒药物和亚临床动脉粥样硬化。在这群人中， 我们将探索与年龄匹配的ART组相比，服用他汀类药物的患者是否有 降低血浆氧化脂蛋白水平和已建立的替代生物标志物和分子标志物 已知的预测和/或导致CVD的M/M和内皮激活。这样的方法可能会减少 尽管抗逆转录病毒治疗，艾滋病毒-1感染的老年人仍然存在过高的发病率和死亡率。这项工作是 创新，对公共健康有潜在影响，并直接解决与老龄化有关的研究重点 慢性艾滋病毒。