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.

项目概要/摘要 与衰老相关的合并症增加，例如动脉粥样硬化性心血管疾病 (CVD) 尽管有有效的抗逆转录病毒治疗（ART），但 HIV-1 感染的新问题仍在出现。目前的治疗方法（例如 他汀类药物）治疗 HIV-1 相关炎症、免疫激活和 CVD 的效果还不够。氧化应激具有 抗氧化剂在 HIV-1 发病机制和 CVD 中发挥着重要作用，但单独使用抗氧化剂不太可能是充分的治疗方法。 有效的抗氧化剂，对多效性炎症介质也具有特定的抗炎作用 氧化脂质 (OxPLs) 可能是改善 HIV-1 相关炎症、免疫的新疗法 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 开发新疗法来管理与艾滋病毒相关的心血管疾病。高密度脂蛋白（HDL）是最重要的 在所有大型流行病学研究中，CVD 都是强有力的独立阴性预测因子。载脂蛋白A-I (apoA-I) 是 HDL 的主要蛋白质，负责大部分抗动脉粥样硬化和抗炎作用 HDL 的特性。这些效应可以通过 apoA-I 肽（例如 4F）来模拟，这些肽是有希望的治疗方法 用于CVD。他汀类药物和 ApoA-I 具有相似的抗炎特性。动物研究证据有限 已表明，与 apoA-I 肽一起服用时，apoA-I 肽的生物学特性得到增强 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发生在肠道水平，这可能是 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 CVD，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。 人类（体内）。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 用作研究他汀类药物和 apoA-I 模拟物的离体/体外协同效应的工具。在本提案中使用 建立具有生理意义的动脉粥样硬化离体模型，我们将探讨以下因素的协同效应 他汀类药物和 ApoA-I 模拟物对确定氧化脂蛋白在慢性病中如何存在的机制的研究 治疗后的 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（目标 1）， M/M 功能障碍（目标 2）和内皮激活（目标 3）。我们还将在体内扩展我们的发现（目标 3）： 接受有效抗逆转录病毒疗法和亚临床动脉粥样硬化的中年/老年人（50-70岁）艾滋病毒携带者。在这个群体中， 我们将探讨与年龄匹配的、未服用他汀类药物的 ART 组相比，服用他汀类药物的参与者是否有 降低氧化脂蛋白的血浆水平并建立替代生物标志物和分子特征 已知 M/M 和内皮细胞激活可预测和/或导致 CVD。这种方法可以减少 尽管接受了抗逆转录病毒治疗，HIV-1感染老年人的发病率和死亡率仍然过高。这部作品是 创新，对公共卫生有潜在影响，并直接解决有关老龄化的研究重点 慢性艾滋病毒。