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

• 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
• 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' -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

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（由申请方提供）：尽管ART具有病毒学抑制作用，但细胞免疫激活和全身炎症水平很少恢复到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-A2 AR- 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CD 39和CD 73水解ATP产生。虽然这些酶在鼠调节性T细胞中共表达，但在人类中，我们已经证实了先前的研究，它们属于单独的CD 4 + T细胞亚群。此外，我们已经观察到HIV-1感染中CD 4 + CD 73 + T细胞的频率和绝对数量的减少，而不管ART的病毒学抑制。CD 4 + CD 73 + T细胞与T细胞免疫活化以及血浆C反应蛋白（CRP）水平负相关。我们推测，由于CD 4 + CD 73 + T细胞的丢失，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、部分交叉的初步研究，评估双嘧达莫（DP）（一种FDA批准的药物，经证实可增加细胞外ADO水平）对细胞免疫激活和炎症的影响。我们将40例接受ART病毒抑制且CD 4 + T细胞计数d500个细胞/mm 3的HIV-1+受试者随机分配至12周DP或安慰剂组。主要终点是共表达CD 38和HLA-DR的CD 8 + T细胞比例和IL-6血浆水平的变化。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：CD 4 + T细胞活化和细胞周期、T细胞成熟亚群频率、单核细胞和巨噬细胞活化、肠粘膜T细胞活化、炎症和凝血生物标志物的血浆水平以及残留病毒表达。在目标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CD 73表达和ADO-A2 AR-cAMP信号通路是否确实可以调节HIV-1相关炎症。我们将确定外周血和肠道粘膜组织中表达CD 73的免疫细胞的频率以及参与信号传导途径的嘌呤水平，并研究它们与免疫激活和炎症的相关性。通过阐明HIV-1相关免疫失调的具体机制，我们的研究结果可能会导致新的干预措施，旨在预防或限制HIV-1感染中慢性炎症和免疫激活的影响。