Effects of IL-6 blockade in treated HIV infection

IL-6 阻断对 HIV 感染治疗的影响

• 批准号: 9005805
• 负责人: MICHAEL MARCEL LEDERMAN
• 金额: $ 160.33万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-13 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005805
• 关键词: Antiviral Agents; Antiviral Therapy; Apoptotic; Attenuated; Automobile Driving; BCL2 gene; Biological Assay; Blood Vessels; Carnitine; Cell Cycle; Cell Death; Cells; Coagulation Process; Data; Disease; Dose; Down-Regulation; Exposure to; Failure; General Population; Genetic study; HIV; HIV Infections; HIV-1; Health; Heart; Homing; Human; IL7R gene; Immune; Immune system; Infection; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; Integrins; Interferons; Interleukin-17; Interleukin-6; Interleukin-7; Intervention Studies; Leukocytes; Link; Lipids; Lymphocyte; Mediating; Metabolism; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Myelogenous; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Plasma; Population Genetics; Positioning Attribute; Proteins; Rheumatoid Arthritis; Role; Signal Transduction; Sorting - Cell Movement; Source; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thromboplastin; Time; brachial artery; cardiovascular risk factor; cell type; clinically relevant; cytokine; disorder risk; heart disease risk; improved; in vivo; indexing; inflammatory marker; inhibitor/antagonist; interleukin-22; intervention effect; lipid metabolism; memory CD4 T lymphocyte; metabolome; metabolomics; microbial; monocyte; mortality; novel; oxidized lipid; oxidized low density lipoprotein; peripheral blood; receptor; resistin; restoration; success; transcriptome; transcriptomics

DESCRIPTION (provided by applicant): We have shown that plasma levels of IL-6 are perhaps the most robust predictors of morbidity and mortality in treated HIV-1 infection. The overall objective of this interventional study is to establish the position of heightened IL-6 exposure on the pathways of pathogenesis and morbidity in treated HIV-1 infected persons with immune failure. We propose 3 aims: I. To examine the effects of IL-6 inhibition on the pathogenesis of immune failure and inflammation in treated HIV infection. Our preliminary data have led us to a novel model of HIV immunopathogenesis where the damaged gut is both the source of high levels of IL-6 and where local and systemic exposure to IL-6 sustains the gut mucosal barrier breach and impairs immune restoration even in the presence of antiviral therapy. This is caused by IL-6 mediated inhibition of the IL-7 receptor � chain - CD127 and IL-6-mediated activation of central memory CD4 T cell cycling and death. We hypothesize that administration of the IL-6 receptor antagonist tocilizumab will decrease the pathologic central memory CD4 T cell cycling and will also restore systemic and gut T cell responses to the homeostatic cytokine IL-7. In the gut and systemically, we will examine the restoration of immune cells, their expression of CD127 and the pro- survival bcl-2 and the gut homing molecule �4�7 that IL-7 induces, the ability of gut cells to express the gut protective molecules IL-22, IL-17 and the effects of this intervention on local and systemic indices of gut mucosal barrier integrity. II. To examine the effect of systemic IL-6 inhibition on indices of cardiovasculr disease (CVD) risk in treated HIV-1 infection. Increased IL-6 levels have been associated with CVD risk in HIV-1 infection and in the general population and genetic studies also demonstrate a role for IL-6 in CVD risk. During IL-6 receptor blockade, we will monitor blood vessel function, levels of insulin resistance, inflammatory lipids and levels of inflammatory and patrolling monocytes that express the clot forming tissue factor. We will relate them to the effects of IL-6 inhibition on targeted inflammatory markers to be studied in Sp Aim 1 and to the activation pathways that comprise the transcriptomic and metabolomic approaches in Sp Aim 3. III. To examine the effects of systemic IL-6 inhibition on the inflammatory transcriptome and plasma metabolomes in treated HIV-1 infection. Our detailed transcriptional analysis of circulating white blood cells in immune failure patients has found a proinflammatory signature reflective of increased IL-6 exposure and also a strong type 1 interferon signature. At the same time the plasma metabolome in immune failure is consistently distinguishable from those of immune successes and healthy controls with profound perturbations in lipid metabolism with the greatest abnormalities seen in subjects with the highest plasma IL-6 levels. We will examine the effects of IL-6 receptor blockade on the peripheral blood leukocyte transcriptome and plasma metabolome and relate these to functional assays of immune pathogenesis and cardiovascular risk.

描述(由申请人提供)：我们已经证明，血浆IL-6水平可能是治疗的HIV-1感染中发病率和死亡率最可靠的预测因子。这项干预性研究的总体目标是确定IL-6暴露增加在治疗的HIV-1感染者免疫失败的发病和发病途径中的地位。我们提出了3个目标：1.检测IL-6抑制在治疗HIV感染中免疫衰竭和炎症发病机制中的作用。我们的初步数据使我们找到了一种新的HIV免疫发病机制模型，在这种模型中，受损的肠道既是高水平IL-6的来源，也是局部和全身暴露于IL-6的地方，维持肠道粘膜屏障的破坏，并损害免疫恢复，即使存在抗病毒治疗。这是由于IL-6介导的IL-7受体CD127链的抑制和IL-6介导的中枢记忆�的激活和T细胞的死亡。我们假设，给予IL-6受体拮抗剂tocilizumab将减少病理中枢记忆CD4T细胞周期，并将恢复全身和肠道T细胞对稳态细胞因子IL-7的反应。在肠道和系统中，我们将检测免疫细胞的恢复，IL-7诱导的免疫细胞表达CD127和支持生存的bcl2和肠道归巢分子�4�7，肠道细胞表达肠道保护分子IL-22和IL-17的能力，以及这种干预对肠道粘膜屏障完整性的局部和系统指标的影响。2.检测全身应用IL-6抑制对HIV-1感染患者心血管疾病风险指标的影响。在HIV-1感染和普通人群中，IL-6水平的升高与心血管疾病风险有关，遗传研究也表明IL-6在心血管疾病风险中的作用。在IL-6受体阻断期间，我们将监测血管功能、胰岛素抵抗水平、炎性血脂以及表达凝块形成组织因子的炎症和巡逻单核细胞水平。我们将与IL-6抑制对Sp Aim 1中靶向炎症标志物的影响以及Sp Aim 3中转录和代谢途径的激活途径有关。III.检测全身IL-6抑制对HIV-1感染治疗中炎性转录组和血浆代谢组的影响。我们对免疫衰竭患者循环白细胞的详细转录分析发现，促炎症特征反映了IL-6暴露的增加，也是强烈的1型干扰素特征。同时，免疫失败的血浆代谢组与免疫成功组和健康对照组的血浆代谢组一致，具有严重的脂代谢紊乱，其中最大的异常出现在血浆IL-6水平最高的受试者中。我们将检测IL-6受体阻断对外周血白细胞转录组和血浆代谢组的影响，并将其与免疫发病机制和心血管风险的功能分析相联系。