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：
9231368
负责人：
Bernard Jonas C Macatangay
金额：
$ 65.26万
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 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231368
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 CD8-Positive T-Lymphocytes 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 Cell Activation Immune System Diseases Immune System and Related Disorders 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 Therapeutic Tissues Transient Ischemic Attack Translating Trauma Viral Viremia antiretroviral therapy arm brachial artery cytokine effective therapy endothelial dysfunction extracellular immune activation immunoregulation improved in vivo monocyte nanomolar peripheral blood prevent public health relevance receptor response reuptake virology

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）：尽管抑制了ART的病毒学抑制，但细胞免疫激活和全身性炎症的水平很少恢复到HIV-1-官方的个体中看到的水平。我们认为，HIV-1+个体中细胞外腺苷（ADO）产生的缺陷在无法抑制慢性HIV-1相关炎症的Ado-A2ar-CAMP信号传导途径中起着重要作用。细胞外ADO是通过胞外酶CD39和CD73水解ATP的应力条件产生的。尽管这些酶在鼠调节T细胞中共表达，但在人类中，我们已经证实了它们以前的研究，即它们属于单独的CD4+ T细胞亚群。此外，我们已经观察到HIV-1感染中CD4+ CD73+ T细胞的频率和绝对数量的减少，而与ART的病毒抑制作用无关。 CD4+ CD73+ T细胞与T细胞免疫激活以及C反应蛋白（CRP）的血浆水平呈负相关。我们假设由于CD4+ CD73+ T细胞的丧失，ADO产生的降低导致无法控制HIV-1感染中慢性炎症的Ado信号途径。我们建议进行I/II期，随机，双盲，安慰剂控制的部分跨界试验研究，以评估二吡啶胺（DP）的影响，这是一种FDA批准的药物，该药物证明会增加细胞外ADO水平，对细胞外免疫激活和炎症。我们将在ART上病毒抑制和CD4+ T细胞计数D500细胞/mm3，将40个HIV-1+受试者随机抑制至DP或安慰剂的12周。主要终点是CD8+ T细胞共表达CD38和HLA-DR的比例的变化以及IL-6的血浆水平。次要终点将评估12和24周DP治疗对免疫学和病毒学参数的影响，包括：CD4+ T细胞激活和细胞循环，T细胞成熟子集的频率，单核细胞和巨噬细胞激活，肠粘膜T细胞活化，生物标志物的血浆水平炎症和凝结，以及残留的病毒表达。在AIM 2中，我们将确定各种免疫学参数的变化是否会转化为可测量的临床结果。因此，我们将在我们的临床试验中评估DP治疗是否可以通过对HIV-1+受试者进行肱动脉流介导的扩张来改善血管功能。在AIM 3中，由于我们已经在体外表明ADO可以抑制T细胞激活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训练营信号传导是否确实可以调节HIV-1相关炎。我们将确定在外周血和肠粘膜组织中表达CD73的免疫细胞的频率，以及信号传导途径中涉及的嘌呤水平，并研究它们与免疫激活和炎症的关联。通过阐明负责HIV-1相关免疫失调的特定机制，我们的研究结果可能会导致新的干预措施，以防止或限制HIV-1感染中慢性炎症和免疫激活的影响。