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: 10162645
• 负责人: Tricia Helen Burdo
• 金额: $ 61.3万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162645
• 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：动脉粥样硬化相关心血管疾病（CVD）是目前最常见的心血管疾病之一。 接受有效抗逆转录病毒治疗 (ART) 的艾滋病毒感染者 (PLWH) 死亡的主要原因。我们的 目前对 HIV 相关动脉粥样硬化发病机制的了解有限且大部分已获得 从临床观察。 HIV引起的动脉粥样硬化的独特病理特征是非钙化 更容易破裂的炎症斑块。在接受 ART 治疗的患者中，HIV 感染不仅 激活免疫细胞，例如巨噬细胞 (MC)，同时也激活一系列分子途径，例如 炎症小体途径，包括 caspase-1 (casp-1) 激活。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得到广泛研究。 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 相关的 CVD。为了实现这一未实现的目标，我们组建了一个多学科的团队 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 (Mɸ) 生物学），以及 Co-I Gordon 博士（HIV-1 感染专家）。通过这一共同努力，我们 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 Tg26） 携带包含大部分 gag 和 pol 基因的缺失，使其无传染性。 Tg26 小鼠模拟 接受抗逆转录病毒疗法的慢性艾滋病患者，其中没有病毒复制，但仍会产生病毒蛋白。为了 为了将 Tg26 引入动脉粥样硬化背景，我们将该品系与载脂蛋白 E (ApoE-/-) 小鼠（一种 过去 25 年用于研究动脉粥样硬化形成的常见小鼠品系，产生了 Tg26/ApoE-/- 小鼠。 我们的初步结果表明 1) Tg26/ApoE-/- 在正常肾功能下加速动脉粥样硬化形成 功能，2) Tg26/ApoE-/- 外周血单核细胞中 casp-1 活化显着较高 (PBMC) 和斑块比 ApoE-/-，3) Tg26/ApoE-/- 中的 HIV-1 转基因促进 MC 形成泡沫细胞， 动脉粥样硬化形成的标志，4) HIV-1 感染患者斑块中的 MC 上的 Casp-1 被激活，并且 5) Tg26 中血清 IL-1β 和 IL-18 升高，HIV+ 患者中 IL-18 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激活 途径，导致 HIV 相关的动脉粥样硬化形成。为了检验这个假设，我们建议调查 通过使用动物模型和现有的 HIV 标本来研究 HIV-1 相关动脉粥样硬化的发病机制。我们 将使用多种新颖的模型和方法，包括我们新建立的 HIV-1 Tg-26 转基因小鼠 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）下维持 泡沫细胞形成系统。拟议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。