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: 10413007
• 负责人: Theodoros Kelesidis
• 金额: --
• 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/10413007
• 关键词: AIDS/HIV problem; Address; Affect; Age; Aging; Animals; Anti-Inflammatory Agents; 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; 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; United States National Institutes of Health; Work; aged; antiretroviral therapy; base; biomarker signature; cardiovascular disorder risk; cardiovascular disorder therapy; cohort; comorbidity; 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; therapeutically effective; 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 与衰老相关的合并症增加，例如动脉粥样硬化心血管疾病（CVD）是一种 尽管有效的抗逆转录病毒疗法（ART），HI​​V-1感染的新兴问题。当前疗法（例如 他汀类药物）为治疗与HIV-1相关的炎症，免疫激活和CVD不足。氧化应激具有 HIV-1发病机理和CVD中的主要作用，但仅抗氧化剂就不可能是足够的治疗。 有效的抗氧化剂也具有针对全质炎症介质的特定抗炎作用 称为氧化脂质（OXPLS）可能是改善HIV-1相关炎症，免疫的新型疗法 激活和CVD。揭示氧化脂质如何影响CVD和HIV-1发病机理，可能有助于 开发管理与HIV相关CVD的新疗法。高密度脂蛋白（HDL）最多 在所有大型流行病学研究中，CVD的强大独立负面预测指标。载脂蛋白A-I （apoa-i），HDL的主要蛋白 HDL的属性。这些效果可以通过有希望的治疗方法来模仿ApoA-1肽，例如4F 对于CVD。他汀类药物和apoa-I具有相似的抗炎特性。动物研究的有限证据 已经表明，当给予apoA-1肽的生物学特性增强 他汀类药物。 apoa-i mimetics和ptatins之间的协同作用可能部分是肠道 动脉粥样硬化的重要调节剂。单核细胞/巨噬细胞（m/m）在 HIV-1免疫致病发生，肠道生物学，动脉粥样硬化。鉴于HIV-1相关的复杂发病机理 CVD，不可能研究他汀类药物和apoa-i mimetics之间协同作用的确切机制 人类（体内）。在UCLA内建立的患者队列，原代人细胞和脂蛋白可以是 用作他汀类药物和apoa-i Mimetics的体内/体外协同作用的工具。在此提案中，使用 建立的生理意义有意义的动脉粥样硬化模型，我们将探讨 他汀类药物和apoa-i模拟物在确定慢性中存在氧化脂蛋白的机制上 治疗的HIV-1感染直接导致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（AIMS 2）和内皮激活（AIM 3）。我们还将在体内扩展我们的发现（AIM 3） 中年/年龄较大（50-70岁）HIV+有效艺术和亚临床动脉粥样硬化的人。在这个小组中， 我们将探讨是否与年龄相比，不汀类药物的艺术小组，他汀类药物的参与者有 氧化脂蛋白的血浆水平较低，并确定了替代生物标志物和分子特征 已知可以预测和/或导致CVD的M/M和内皮激活。这样的方法可以减少 尽管HIV-1感染了老年人，但仍剩下过多的发病率和死亡率。这项工作是 创新，对公共卫生有潜在的影响，并直接解决有关衰老的研究重点 慢性艾滋病毒。