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，IL-6的血浆水平可能是治疗后HIV-1感染的发病率和死亡率最可靠的预测因子。本介入性研究的总体目标是确定IL-6暴露升高在免疫功能衰竭的HIV-1感染者发病和发病途径中的地位。我们提出了三个目标：1 .研究IL-6抑制对HIV感染治疗后免疫功能衰竭和炎症发病机制的影响。我们的初步数据使我们建立了一种新的HIV免疫发病机制模型，其中受损的肠道既是高水平IL-6的来源，而且即使在抗病毒治疗的存在下，局部和全身暴露于IL-6也会维持肠道粘膜屏障的破坏并损害免疫恢复。这是由IL-6介导的IL-7受体链- CD127的抑制和IL-6介导的中枢记忆CD4 T细胞循环和死亡的激活引起的。我们假设给予IL-6受体拮抗剂tocilizumab会减少病理性中枢记忆CD4 T细胞周期，也会恢复全身和肠道T细胞对稳态细胞因子IL-7的反应。在肠道和系统中，我们将研究免疫细胞的恢复，它们对CD127的表达以及IL-7诱导的促生存bcl-2和肠道归巢分子4 -7的表达，肠道细胞表达肠道保护分子IL-22、IL-17的能力，以及这种干预对肠道粘膜屏障完整性局部和全身指标的影响。2。目的：探讨全身IL-6抑制对HIV-1感染患者心血管疾病（CVD）风险指标的影响。在HIV-1感染和普通人群中，IL-6水平升高与心血管疾病风险相关，遗传学研究也表明IL-6在心血管疾病风险中起作用。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，炎症脂质水平以及表达凝块形成组织因子的炎症和巡逻单核细胞水平。我们将把它们与Sp Aim 1中研究的IL-6抑制对靶向炎症标志物的影响以及Sp Aim 3中包括转录组学和代谢组学方法的激活途径联系起来。3。研究IL-6抑制对治疗后HIV-1感染的炎症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，促炎特征反映了IL-6暴露增加和1型干扰素的强烈特征。与此同时，免疫失败的血浆代谢组与免疫成功和健康对照的血浆代谢组一致，脂质代谢受到严重干扰，血浆IL-6水平最高的受试者出现最大异常。我们将研究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联系起来。