Effect of IL-1B inhibition on inflammation and cardiovascular risk in HIV

项目简介：虽然抗逆转录病毒治疗延长了生命，但并不能完全恢复健康。由于仍有争议的原因，接受良好治疗的艾滋病毒感染者的寿命比未感染的人短，而且患包括心血管疾病在内的一些“非艾滋病”疾病的风险也高于预期。hiv感染者发生心肌梗死的风险高出2倍，心源性猝死的发生率也更高。虽然这些临床观察的潜在机制可能是多因素的，但在治疗HIV感染的情况下，慢性炎症已成为疾病过程的关键因素。IL-1是一种由单核细胞、巨噬细胞和树突状细胞产生的促炎细胞因子；canakinumab是一种针对IL-1的单克隆抗体，使用canakinumab抑制IL-1可显着降低炎症标志物，并且在CANTOS研究中已在bbb8500例无HIV的个体中进行了研究。为了确定长期抗逆转录病毒治疗的HIV感染期间IL-1抑制对全身性炎症的影响，我们建议进行一项以单中心发病机制为导向的研究，评估canakinumab（一种抑制IL-1的人单克隆抗体）对全身性炎症、T细胞活化和血管炎症的影响。鉴于炎症在促进病毒持久性方面的假定作用，我们还将测量canakinumab对HIV储存库大小的影响。我们将进行一项随机双盲安慰剂对照概念验证临床试验，评估canakinumab用于长期接受抗逆转录病毒治疗且HIV RNA水平检测不到的患者的安全性和效果。我们提出以下目标：目的1：确定在有效治疗和抑制HIV感染的成人中使用canakinumab抑制IL-1的安全性、耐受性和药代动力学。我们将在10名患者中进行初步试点研究，他们都将接受单剂量canakinumab；如果药物安全且耐受性良好（如预期），我们将在Aims 1-3下随机招募100名额外的安慰剂对照试验；目的2：证明IL-1抑制降低炎症标志物和单核细胞活化，改善血管炎症和内皮功能障碍在治疗和抑制hiv感染者；目的3：确定IL-1抑制是否会降低T细胞活化并降低血液中HIV储存库的大小。该应用程序结合了(1)一个具有强大合作记录的专业和成功的多学科团队，(2)从现有的艾滋病毒感染受试者队列中快速招募受试者的能力，(3)高级研究人员的合作，进行创新的免疫学分析和艾滋病毒持久性测量。

DESCRIPTION (provided by applicant): Project Summary Although antiretroviral therapy prolongs life, it does not fully restore health. For reasons that remain controversial, HIV-infecte individuals doing well on therapy have a shortened lifespan as compared to their uninfected counterparts and also have a higher than expected risk of a number of "non-AIDS" conditions including cardiovascular disease. HIV-infected individuals have a 2-fold higher risk of myocardial infarction and higher rates of sudden cardiac death. While the underlying mechanism for these clinical observations is likely multifactorial, chronic inflammation in the setting of treated HIV infection has emerged as a key contributor to the disease process. IL-1� is a pro-inflammatory cytokine produced by monocytes, macrophages and dendritic cells; IL-1� inhibition using canakinumab, a monoclonal antibody to IL-1�, dramatically reduces inflammatory markers, and has been studied in > 8500 individuals without HIV in the CANTOS study. In order to determine the impact of IL-1� inhibition on systemic inflammation during long-term antiretroviral-treated HIV infection, we propose to perform a single center pathogenesis-oriented study assessing the impact of canakinumab-a human monoclonal antibody which inhibits IL-1�-on systemic inflammation, T cell activation, and vascular inflammation. Given the putative role that inflammation has in contributing to viral persistence, we will also measure the impact of canakinumab on the size of the HIV reservoir. We will perform a randomized double-blinded placebo-controlled proof-of-concept clinical trial evaluating the safety and effects of canakinumab administered to long-term antiretroviral treated patients who have undetectable HIV RNA levels. We propose the following aims: Aim 1: To determine the safety, tolerability, and pharmacokinetics of IL-1� inhibition using canakinumab in effectively treated and suppressed HIV infected adults. We will perform an initial pilot study in ten individuals who will all receivea single dose of canakinumab; if the drug is safe and well tolerated (as expected), we will enroll 100 additional individuals in a randomized, placebo controlled trial under Aims 1-3; Aim 2: To demonstrate that IL-1� inhibition decreases inflammatory markers and monocyte activation, and improves vascular inflammation and endothelial dysfunction among treated and suppressed HIV-infected individuals; Aim 3: To determine whether IL-1� inhibition reduces T cell activation and decreases the size of the HIV reservoir in blood. This application combines (1) a dedicated and successful multidisciplinary team with a strong record of collaboration, (2) the ability to rapidly recruit subjects from existing cohorts of HIV-infected subjects, (3) the collaboration of senior investigators performing innovative immunology assays and measurements of HIV persistence.