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: 9751953
• 负责人: Tricia Helen Burdo
• 金额: $ 61.05万
• 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/9751953
• 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 Cell Activation; Immune System Diseases; In Vitro; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; 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; 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 (Mϕ) 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-1 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.

项目摘要/摘要：动脉粥样硬化相关的心血管疾病（CVD）目前是其中之一 在有效的抗逆转录病毒疗法（ART）的艾滋病毒（PLWH）患者中死亡的主要原因。我们的 目前，了解与HIV相关的动脉粥样硬化的发病机理是有限的，并且在很大程度上得到了 从临床观察。 HIV诱导的动脉粥样硬化的独特病理特征是未定量的 炎症斑块更容易破裂。在艺术治疗的患者中，艾滋病毒感染不仅 激活免疫细胞，例如巨噬细胞（MC），但也激活一系列分子途径 炎性途径，包括caspase-1（CASP-1）激活。但是，确切的细胞和 尚未广泛研究与HIV相关的动脉粥样硬化基础的分子机制。 了解这些机制将有助于更好地开发和设计新颖的治疗干预措施 治疗/预防HIV相关的CVD。为了实现这个未满足的目标，我们已经形成了一个多学科的目标 由多个PIS QIN博士（先天免疫和CVD专家）和Burdo博士组成的团队（HIV-1 CVD专家 和巨噬细胞（Mϕ）生物学）和戈登博士（HIV-1感染专家）。通过这项共同的努力，我们 是否使用了携带7.4-kb供应HIV DNA构建体的HIV-转基因小鼠（B6背景的TG26） 携带删除，涵盖大多数插科打and基因，以使其不感染。 TG26小鼠模仿 慢性HIV患者在没有病毒复制的ART上，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，我们用载脂蛋白E（apoe - / - ）小鼠越过这条线 在过去25年中，用于研究动脉粥样硬化的常见小鼠菌株，用于产生TG26/APOE - / - 小鼠。 我们的初步结果表明1）TG26/apoE - / - 开发了一种正常肾脏的加速动脉粥样硬化 功能，2）TG26/apoE - / - 在外周血单核细胞中的CASP-1激活明显更高 （PBMC）和斑块比APOE-/ - ，3）TG26/APOE-/ - 促进MC中的HIV-1转换形成泡沫细胞， 动脉粥样硬化的标志，4）在HIV-1感染患者的斑块中，在MC上激活了CASP-1，并且被激活 5）在TG26中，血清IL-1和IL-18升高，IL-18升高HIV+患者，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，导致与HIV相关的动脉粥样硬化。为了检验这一假设，我们建议调查 通过使用动物模型和可用的HIV标本，HIV-1相关的动脉粥样硬化的发病机理。我们 将使用几种新型模型和方法，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包括我们已建立的体外模型在内的标准方法 泡沫细胞形成的系统。拟议的研究将为我们的理解提供重要的见解 HIV-1感染和免疫激活在动脉粥样硬化中的作用。