Host genetic predictors of plasma IL-1b levels and pharmacogenomics of in vivo IL-1b blockade during treated HIV disease

HIV 治疗期间血浆 IL-1b 水平的宿主遗传预测因子和体内 IL-1b 阻断的药物基因组学

• 批准号: 10409570
• 负责人: Sulggi Angela Lee
• 金额: $ 80.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409570
• 关键词: Acquired Immunodeficiency Syndrome; Age; Aging; Anti-Inflammatory Agents; Antibodies; Biological Assay; Biological Markers; C-reactive protein; CD14 gene; CD4 Positive T Lymphocytes; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Cryopreservation; Custom; DNA; Data; Data Set; Disease; Disease Progression; Dose; Epidemiology; Event; Flow Cytometry; Future; General Population; Genes; Genetic; Genetic Transcription; HIV; HIV Seronegativity; HIV antiretroviral; Immune; Immune System Diseases; Immunologics; Incidence; Individual; Inflammation; Interferon Type II; Interleukin-1 beta; Interleukin-10; Interleukin-18; Interleukin-6; Interleukins; Life Expectancy; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; Monoclonal Antibodies; Morbidity - disease rate; Myocardial Infarction; Nucleic Acid Regulatory Sequences; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacogenomics; Phenotype; Pilot Projects; Plasma; Play; Population; Proteins; RNA; Research; Residual state; Resolution; Risk; Role; Sampling; Signal Transduction; Stroke; System; Testing; Validation; Variant; Virus; Work; adjudicate; antiretroviral therapy; base; cardiovascular disorder risk; cardiovascular risk factor; clinical predictors; cohort; comorbidity; cytokine; differential expression; epidemiology study; exome sequencing; experience; genetic predictors; genome wide association study; genome-wide; high dimensionality; in vivo; inflammatory marker; monocyte; mortality; multiple omics; multiplex assay; new therapeutic target; novel; novel strategies; phase I trial; protein expression; response; systemic inflammatory response; treatment response; vascular inflammation

PROJECT SUMMARY/ ABSTRACT Despite effective antiretroviral therapy (ART), HIV-infected individuals have reduced life expectancy and a higher incidence of aging-associated diseases compared to HIV-uninfected controls. Persistent systemic inflammation despite suppressive ART has been associated with serious non-AIDS morbidity (e.g., myocardial infarction, stroke, malignancy) and mortality. Recent data suggests that an upstream regulator of interleukin (IL)-6, interleukin-1 beta (IL-1β), may be the major driver of increased cardiovascular risk observed in HIV+ ART-suppressed individuals. The recent CANTOS trial has now demonstrated in over 10,000 individuals that in vivo IL-1β blockade with the monoclonal antibody canakinumab significantly reduced cardiovascular events and cancer mortality in the general population. We have recently performed a phase 1 trial administering a single dose of canakinumab to HIV+ ART-suppressed participants and found that in vivo IL-1β blockade led to significant reductions in plasma IL-1β (as well as associated systemic inflammatory markers plasma IL-6 and high sensitivity C-reactive protein), vascular inflammation, and monocyte activation. Furthermore, our ex vivo data suggests that IL- β plays a critical role in maintaining the “HIV reservoir” (the total amount of residual virus that persists during ART suppression and potentially drives systemic inflammation). We will use an unbiased integrated approach that combines several high dimensional datasets to test the hypothesis that IL-1β triggers the proinflammatory response that fuels HIV immune dysfunction and persistence. Our proposed study will be the first (in HIV+ or HIV-uninfected individuals) to pursue the link between host genetics and plasma IL-1β levels – while simultaneously assaying several proinflammatory cytokines in this pathway, including IL-6 and IL-18. In Aim 1 we will identify DNA variants associated with plasma IL-1β in 1,000 HIV+ ART-suppressed participants from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort using custom whole exome sequencing to add to existing genomewide array data. Individuals with extreme phenotypes (highest and lowest deciles of plasma IL-1β levels) will then be selected for functional validation in Aim 2 using a novel approach that simultaneously characterizes RNA and protein expression at single cell resolution using single cell RNA and antibody sequency (scRNA-Abseq). Finally, we will perform functional in vivo validation of identified genes associated with IL-1β signaling, leveraging samples from our phase 1 trial of canakinumab in Aim 3. Therefore, we will functionally validate findings from Aim 1 as well as identify novel genes/pathways by studying individuals with unique HIV+ phenotypes (extreme plasma IL-1β levels and after canakinumab treatment, respectively) in Aims 2 and 3. The proposed work will identify specific genes and immune pathways that may act synergistically with IL-1β, identifying novel therapeutic targets that may be broadly applicable for the treatment of inflammation-associated diseases in HIV+ and non-HIV populations.

项目概要/摘要 尽管抗逆转录病毒治疗 (ART) 有效，但 HIV 感染者的预期寿命仍然缩短，并且 与未感染艾滋病毒的对照组相比，衰老相关疾病的发生率更高。 尽管采用抑制性抗逆转录病毒疗法，但炎症仍与严重的非艾滋病发病率（例如心肌梗死）相关。 最近的数据表明白细胞介素的上游调节因子。 (IL)-6、白介素-1β (IL-1β) 可能是 HIV+ 患者心血管风险增加的主要驱动因素 最近的 CANTOS 试验现已在 10,000 多名受 ART 抑制的个体中证明， 使用单克隆抗体 canakinumab 体内 IL-1β 阻断可显着减少心血管事件 我们最近进行了一项 1 期试验，使用 对 HIV+ ART 抑制的参与者进行单剂量卡那奴单抗，发现体内 IL-1β 阻断导致 血浆IL-1β（以及相关的全身炎症标志物血浆IL-6和 高敏感性 C 反应蛋白）、血管炎症和单核细胞激活此外，我们的离体。 数据表明，IL-β在维持“HIV病毒库”（残留病毒总量）方面发挥着关键作用。 在 ART 抑制期间持续存在并可能导致全身炎症）。 综合方法，结合多个高维数据集来测试 IL-1β 触发的假设 我们提出的研究将是促进艾滋病毒免疫功能障碍和持久性的促炎症反应。 第一个（在 HIV+ 或未感染 HIV 的个体中）探索宿主遗传学与血浆 IL-1β 之间的联系 水平 – 同时测定该途径中的几种促炎细胞因子，包括 IL-6 和 在目标 1 中，我们将在 1,000 名接受 ART 抑制的 HIV+ 患者中鉴定与血浆 IL-1β 相关的 DNA 变异。 来自艾滋病研究中心网络综合临床系统 (CNICS) 队列的参与者使用 定制全外显子组测序以添加到现有的全基因组阵列数据中。 然后将选择表型（血浆 IL-1β 水平的最高和最低十分位数）进行功能验证 目标 2 使用一种同时表征单细胞 RNA 和蛋白质表达的新方法 使用单细胞 RNA 和抗体序列 (scRNA-Abseq) 进行分辨率最后，我们将执行功能。 利用我们 1 期试验的样本，对已识别的与 IL-1β 信号传导相关的基因进行体内验证 目标 3 中的 canakinumab。因此，我们将从功能上验证目标 1 的发现并确定新的 通过研究具有独特 HIV+ 表型的个体（极端血浆 IL-1β 水平和之后 目标 2 和 3 中的卡那奴单抗治疗分别）。拟议的工作将识别特定基因和 可能与 IL-1β 协同作用的免疫途径，确定可能的新治疗靶点 广泛适用于治疗 HIV+ 和非 HIV 人群的炎症相关疾病。