Effects of IL-6 blockade in treated HIV infection

描述（由申请人提供）：我们已经表明，血浆IL-6水平可能是治疗的HIV-1感染中发病率和死亡率的最可靠预测因子。这项干预性研究的总体目标是确定IL-6暴露增加在免疫失败的经治疗HIV-1感染者发病和发病途径中的地位。我们提出三个目标：一。研究IL-6抑制剂对HIV感染患者免疫衰竭和炎症发病机制的影响。我们的初步数据使我们获得了一种新的HIV免疫发病机制模型，其中受损的肠道是高水平IL-6的来源，并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破坏并损害免疫恢复。这是由IL-6介导的IL-7受体链-CD 127的抑制和IL-6介导的中枢记忆CD 4 T细胞循环和死亡的激活引起的。我们假设给予IL-6受体拮抗剂托珠单抗将降低病理性中央记忆CD 4 T细胞循环，并恢复全身和肠道T细胞对稳态细胞因子IL-7的应答。在肠道和全身，我们将检查免疫细胞的恢复，它们的CD 127和促生存bcl-2和IL-7诱导的肠道归巢分子<$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的局部和全身指数的影响。二.检测全身性IL-6抑制对经治疗的HIV-1感染者心血管疾病（CVD）风险指数的影响。IL-6水平升高与HIV-1感染中的CVD风险相关，在一般人群中，遗传研究也证明了IL-6在CVD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、炎症脂质以及表达凝块形成组织因子的炎症和巡逻单核细胞水平。我们将它们与IL-6抑制对SP Aim 1中研究的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相关。三.研究全身性IL-6抑制对经治疗的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的循环白色血细胞的详细转录分析发现了反映IL-6暴露增加的促炎特征，以及强烈的1型干扰素特征。同时，免疫失败中的血浆代谢组始终与免疫成功和健康对照中的血浆代谢组不同，其中脂质代谢严重紊乱，在具有最高血浆IL-6水平的受试者中观察到最大的异常。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测定相关。

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.