Role of caspase-1 activation in HIV-1 associated atherogenesis

Caspase-1 激活在 HIV-1 相关动脉粥样硬化形成中的作用

• 批准号: 9923758
• 负责人: Tricia Helen Burdo
• 金额: $ 61.29万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923758
• 关键词: AIDS prevention; Ablation; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Autopsy; Biological Markers; Biological Models; Biology; Body Weight; Bone Marrow Transplantation; CASP1 gene; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Complex; Complication; DNA; Development; Endothelium; Event; Foam Cells; Fostering; Foundations; GAG Gene; Goals; HIV; HIV Infections; HIV-1; High Fat Diet; Human; Hyperlipidemia; Immune; Immune System Diseases; In Vitro; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Interleukin-18; Joints; Lipids; Macrophage Activation; Mediating; Modeling; Molecular; Mouse Strains; Mus; Myeloid Cells; Natural Immunity; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Prevention; Renal function; Role; Rupture; Serum; Signal Transduction; Specimen; Splenocyte; T-Lymphocyte; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Viral Proteins; Virus Replication; antiretroviral therapy; apolipoprotein E-3; atherogenesis; coronary plaque; design; immune activation; in vitro Model; insight; lymph nodes; macrophage; molecular array; monocyte; mortality; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; pol genes; vascular inflammation

Project summary/Abstract: Atherosclerosis-associated cardiovascular disease (CVD) is currently one of the leading causes of mortality among people living with HIV (PLWH) on effective antiretroviral therapy (ART). Our current understanding of the pathogenesis of HIV-associated atherosclerosis is limited and largely obtained from clinical observations. The distinct pathologic features of HIV-induced atherosclerosis are noncalcified inflammatory plaques that are more vulnerable to rupture. In patients on ART treatment, HIV infection not only activates immune cells, such as macrophages (MC), but also activates an array of molecular pathways, such the inflammasome pathway, including caspase-1 (casp-1) activation. However, the exact cellular and molecular mechanisms underlying HIV-associated atherogenesis have not been extensively investigated. Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the treatment/prevention of HIV-associated CVD. To achieve this unmet goal, we have formed a multidisciplinary team consisting of multiple PIs Dr. Qin (innate immunity and CVD expert) and Dr. Burdo (expert in HIV-1 CVD and macrophage (Mɸ) biology), and Co-I Dr. Gordon (expert in HIV-1 infection). Through this joint effort, we have utilized HIV-transgenic mice (Tg26 on a B6 background) carrying a 7.4-kb proviral HIV DNA construct carrying a deletion, encompassing most of the gag and pol genes, to render it noninfectious. Tg26 mice mimic chronic HIV patients on ART in which there is no viral replication, but viral proteins are still produced. In order to introduce Tg26 to an atherogenic background, we crossed this line with Apolipoprotein E (ApoE-/-) mice, a common mouse strain used for studying atherogenesis for the last 25 years to generate Tg26/ApoE-/- mice. Our preliminary results show that 1) Tg26/ApoE-/- developed an accelerated atherogenesis with normal renal function, 2) Tg26/ApoE-/- had significantly higher casp-1 activation in peripheral blood mononuclear cells (PBMC) and plaques than ApoE-/-, 3) The HIV-1 transgene in Tg26/ApoE-/- fostered MC to form the foam cells, a hallmark of atherogenesis, and 4) Casp-1 is activated on MC in the plaques of HIV-1-infected patients, and 5) serum IL-1β and IL-18 are elevated in Tg26 and IL-18 is elevated in HIV+ patients and correlates with coronary plaque. Therefore, we hypothesize that chronic HIV infection induces MC activation via casp-1 pathway, contributing to HIV-associated atherogenesis. To test this hypothesis, we propose to investigate the pathogenesis of HIV-1-associated atherosclerosis by using animal models and available HIV specimens. We will use several novel models and approaches including our newly established HIV-1 Tg-26 transgenic mice maintained under hyperlipidemia conditions as well as standard approaches including our established in vitro model systems for foam cell formation. The proposed studies will provide important insights into our understanding of the role of HIV-1 infection and immune activation in atherosclerosis.

项目概要/摘要：动脉粥样硬化相关性心血管疾病（CVD）是目前研究的热点之一。 艾滋病毒感染者（PLWH）在接受有效的抗逆转录病毒疗法（ART）后死亡的主要原因。我们 目前对HIV相关动脉粥样硬化的发病机制的理解是有限的 临床观察。HIV诱导的动脉粥样硬化的明显病理特征是非钙化 更容易破裂的炎性斑块。在接受抗逆转录病毒治疗的患者中，艾滋病毒感染不仅 激活免疫细胞，如巨噬细胞（MC），但也激活一系列分子途径，如 炎性体途径，包括半胱天冬酶-1（casp-1）活化。然而，确切的细胞和 HIV相关动脉粥样硬化形成的分子机制尚未被广泛研究。 了解这些机制将有助于更好地开发和设计新的治疗干预措施， 治疗/预防HIV相关CVD。为了实现这一未实现的目标，我们成立了一个多学科的 由多名PI组成的团队秦博士（先天免疫和CVD专家）和Burdo博士（HIV-1 CVD专家） 和巨噬细胞（M细胞）生物学），以及Co-I博士戈登（HIV-1感染专家）。通过这一共同努力，我们 已经利用携带7.4-kb前病毒HIV DNA构建体的HIV转基因小鼠（B6背景上的Tg 26 携带一个缺失，包括大部分的gag和pol基因，使其无感染性。Tg 26小鼠模拟 接受抗逆转录病毒治疗的慢性艾滋病患者，其中没有病毒复制，但病毒蛋白仍在产生。为了 为了将Tg 26引入致动脉粥样硬化背景，我们将该品系与载脂蛋白E（ApoE-/-）小鼠杂交， 在过去25年中用于研究动脉粥样硬化形成以产生Tg 26/ApoE-/-小鼠的常见小鼠品系。 我们的初步结果表明：1）Tg 26/ApoE-/-在正常肾组织中加速了动脉粥样硬化的形成， 2）Tg 26/ApoE-/-在外周血单个核细胞中具有显著更高的casp-1活化 3）Tg 26/ApoE-/-中的HIV-1转基因促进MC形成泡沫细胞， 4）Casp-1在HIV-1感染患者的斑块中的MC上被激活，和 5)血清IL-1β和IL-18在Tg 26中升高，IL-18在HIV+患者中升高，并与 冠状动脉斑块因此，我们假设慢性HIV感染通过casp-1诱导MC活化， 途径，有助于艾滋病毒相关的动脉粥样硬化。为了验证这一假设，我们建议调查 利用动物模型和现有HIV标本探讨HIV-1相关动脉粥样硬化的发病机制。我们 将使用几种新的模型和方法，包括我们新建立的HIV-1 Tg-26转基因小鼠 维持在高脂血症条件下以及标准方法，包括我们建立的体外模型 用于泡沫泡孔形成的系统。拟议中的研究将为我们理解 HIV-1感染和免疫激活在动脉粥样硬化中的作用