Dipyridamole as a Modulator of HIV-1 Inflammation by Adenosine Regulation

双嘧达莫通过腺苷调节调节 HIV-1 炎症

基本信息

批准号：
8803308
负责人：
Bernard Jonas C Macatangay
金额：
$ 82.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8803308
关键词：
5&apos -Nucleotidase ADORA2A gene Adenosine Adenosine Triphosphate Adenylate Cyclase Aftercare Anticoagulants Aspirin Atherosclerosis Binding Biological Markers Blood Cells Blood Vessels C-reactive protein CD4 Positive T Lymphocytes CD8B1 gene Cardiovascular Diseases Cell Count Cell Cycle Cell Maturation Cells Chronic Chronic Disease Clinical Clinical Trials Coagulation Process Cyclic AMP Defect Development Dipyridamole Disease Progression Double-Blind Method Enzymes Evaluation FDA approved Frequencies HIV HIV-1 HLA-DR Antigens Health Heart Valves Human Hydrolysis Hypoxia Immune Immune System Diseases Immunologics Immunosuppression Immunosuppressive Agents In Vitro Incubated Individual Infection Inflammation Inflammatory Interleukin-6 Intervention Intervention Trial Lead Life Expectancy Macrophage Activation Measurable Measures Mediating Mucous Membrane Mus Nucleoside Transporter Operative Surgical Procedures Outcome Participant Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phase I/II Trial Pilot Projects Placebo Control Placebos Plasma Play Population Postoperative Period Production Purinergic P1 Receptors Purines Randomized Regulation Regulatory T-Lymphocyte Residual state Risk Role Signal Pathway Signal Transduction Stress Stroke prevention T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Therapeutic Tissues Transient Ischemic Attack Translating Trauma Viral Viremia antiretroviral therapy arm brachial artery cytokine effective therapy endothelial dysfunction extracellular immune activation improved in vivo monocyte nano peripheral blood prevent purine receptor response reuptake

项目摘要

DESCRIPTION (provided by applicant): Despite virologic suppression on ART, the levels of cellular immune activation and systemic inflammation rarely return to levels seen in HIV-1-seronegative individuals. We believe that a defect in extracellular adenosine (ADO) production in HIV-1+ individuals plays an important role in the inability of the ADO-A2AR- cAMP signaling pathway to suppress chronic HIV-1-associated inflammation. Extracellular ADO is generated in conditions of stress through hydrolysis of ATP by the ectoenzymes, CD39 and CD73. While these enzymes are co-expressed in murine regulatory T cells, in humans we have confirmed previous studies that they belong in separate CD4+ T cell subsets. Furthermore, we have observed decreases in the frequency and absolute numbers of CD4+CD73+ T cells in HIV-1 infection, regardless of virologic suppression on ART. CD4+CD73+ T cells inversely correlate with T cell immune activation as well as plasma levels of C-reactive protein (CRP). We hypothesize that decreased ADO production, due to the loss of CD4+CD73+ T cells, contributes to the inability of the ADO-signaling pathway to control the chronic inflammation in HIV-1 infection. We propose to conduct a phase I/II, randomized, double blind, placebo controlled, partial crossover pilot study evaluating the effect of Dipyridamole (DP), an FDA-approved drug proven to increase extracellular ADO levels, on cellular immune activation and inflammation. We will randomize 40 HIV-1+ subjects virally suppressed on ART and with CD4+ T cell counts d500 cells/mm3, to 12 weeks of either DP or placebo. The primary endpoints are the changes in the proportion of CD8+ T cell co-expressing CD38 and HLA-DR and the plasma levels of IL-6. Secondary endpoints will assess the impact of 12 and 24 weeks DP therapy on immunologic and virologic parameters including: CD4+ T cell activation and cell cycling, frequencies of T cell maturation subsets, monocyte and macrophage activation, gut mucosal T cell activation, plasma levels of biomarkers of inflammation and coagulation, and residual viral expression. In Aim 2, we will determine whether changes in the various immunologic parameters will translate to a measurable clinical outcome. As such we will evaluate whether DP therapy can improve vascular function by performing brachial artery flow-mediated dilation on the HIV-1+ subjects in our clinical trial. In Aim 3, since we have shown in vitro that ADO can suppress T cell activation and secretion of pro-inflammatory cytokines, we will investigate in vivo whether CD73 expression and the ADO-A2AR-cAMP signaling pathway can indeed regulate HIV-1-associated inflammation. We will determine frequencies of immune cells expressing CD73 in peripheral blood and gut mucosal tissue as well as the levels of the purines involved in the signaling pathway and investigate their associations with immune activation and inflammation. By elucidating specific mechanisms responsible for HIV-1-associated immune dysregulation, results of our study may lead to new interventions aimed at preventing or limiting the impact of chronic inflammation and immune activation in HIV-1 infection.

描述（由申请人提供）：尽管 ART 受到病毒学抑制，但细胞免疫激活和全身炎症的水平很少恢复到 HIV-1 血清阴性个体的水平。我们认为，HIV-1+个体细胞外腺苷（ADO）产生的缺陷在ADO-A2AR-cAMP信号通路无法抑制慢性HIV-1相关炎症中起着重要作用。细胞外 ADO 在应激条件下通过胞外酶 CD39 和 CD73 水解 ATP 产生。虽然这些酶在小鼠调节性 T 细胞中共表达，但在人类中，我们之前的研究已经证实它们属于不同的 CD4+ T 细胞亚群。此外，我们观察到 HIV-1 感染中 CD4+CD73+ T 细胞的频率和绝对数量下降，无论 ART 的病毒学抑制如何。 CD4+CD73+ T 细胞与 T 细胞免疫激活以及血浆 C 反应蛋白 (CRP) 水平呈负相关。我们假设，由于 CD4+CD73+ T 细胞的损失，ADO 产生减少，导致 ADO 信号通路无法控制 HIV-1 感染中的慢性炎症。我们建议进行一项 I/II 期、随机、双盲、安慰剂对照、部分交叉试点研究，评估双嘧达莫 (DP) 对细胞免疫激活和炎症的影响，双嘧达莫 (DP) 是 FDA 批准的药物，被证明可以增加细胞外 ADO 水平。我们将 40 名 HIV-1+ 受试者随机分组，接受 ART 病毒抑制且 CD4+ T 细胞计数为 d500 个细胞/mm3，接受 DP 或安慰剂 12 周。主要终点是共表达 CD38 和 HLA-DR 的 CD8+ T 细胞比例的变化以及血浆 IL-6 水平的变化。次要终点将评估 12 周和 24 周 DP 治疗对免疫学和病毒学参数的影响，包括：CD4+ T 细胞活化和细胞周期、T 细胞成熟子集的频率、单核细胞和巨噬细胞活化、肠粘膜 T 细胞活化、生物标志物的血浆水平炎症和凝血以及残留病毒表达。在目标 2 中，我们将确定各种免疫参数的变化是否会转化为可测量的临床结果。因此，我们将在临床试验中评估 DP 疗法是否可以通过对 HIV-1+ 受试者进行肱动脉血流介导的扩张来改善血管功能。在目标 3 中，由于我们已经在体外证明 ADO 可以抑制 T 细胞活化和促炎细胞因子的分泌，因此我们将在体内研究 CD73 表达和 ADO-A2AR-cAMP 信号通路是否确实可以调节 HIV-1 相关的炎。我们将测定外周血和肠粘膜组织中表达CD73的免疫细胞的频率以及参与信号通路的嘌呤水平，并研究它们与免疫激活和炎症的关系。通过阐明导致 HIV-1 相关免疫失调的具体机制，我们的研究结果可能会带来新的干预措施，旨在预防或限制慢性炎症和免疫激活对 HIV-1 感染的影响。