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: 9917688
• 负责人: Sulggi Angela Lee
• 金额: $ 80.61万
• 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/9917688
• 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; new therapeutic target; novel; novel strategies; phase I trial; protein expression; 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.

项目摘要/摘要 尽管有效的抗逆转录病毒疗法（ART），艾滋病毒感染者的预期寿命降低了， 与HIV未感染的对照相比，与衰老相关疾病的发生率更高。持续的系统性 尽管有抑制性艺术，炎症与严重的非辅助发病有关（例如，心肌 最近的数据表明，白介素的上游调节器 （IL）-6，白介素-1β（IL-1β）可能是HIV+中观察到的心血管风险增加的主要驱动力 被抑制的人。最近的CANTOS审判现已证明了10,000多名 用单克隆抗体canakinumab显着降低心血管事件的体内IL-1β块 和普通人群的癌症死亡率。我们最近进行了管理A期1期试验 单剂量的canakinumab致HIV+ ART抑制的参与者，发现体内IL-1β桶导致 等离子体IL-1β的显着降低（以及相关的全身性炎症标志物等离子IL-6和 高灵敏度C反应蛋白），血管炎症和单核细胞活化。此外，我们的前体体 数据表明，IL-β在维持“ HIV储量”（残留病毒的总量）中起着至关重要的作用 在艺术抑制过程中，这种情况一直存在，并有可能驱动系统注射）。我们将使用公正 集成方法结合了几个高维数据集，以测试IL-1β触发的假设 促进HIV免疫功能障碍和持久性的促炎反应。我们提出的研究将是 第一个（在HIV+或HIV未感染的个体中）纯化宿主遗传学与等离子体IL-1β之间的联系 水平 - 同时在该途径中分析了几种促炎性细胞因子，包括IL-6和 IL-18。在AIM 1中，我们将确定1,000 HIV+ ART抑制的血浆IL-1β相关的DNA变体 艾滋病综合临床系统研究网络（CNIC）队列的参与者使用 自定义整个外显子组测序以添加到现有的全基因组阵列数据中。极端的人 然后将选择表型（血浆IL-1β水平的最高和最低分数）以进行功能验证 AIM 2使用一种新颖的方法，该方法简单地表征了单细胞的RNA和蛋白质表达 使用单细胞RNA和抗体序列（SCRNA-ABSEQ）分辨率。最后，我们将在 体内验证与IL-1β信号相关的鉴定基因，利用我们的1期试验样品 AIM 3中的canakinumab。因此，我们将在功能上验证AIM 1的发现并确定新颖 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），基因/途径 在目标2和3中，分别为canakinumab治疗。拟议的工作将确定特定的基因和 可能与IL-1β协同作用的免疫途径，鉴定出可能是的新型治疗靶标 广泛适用于HIV+和非HIV种群中与炎症相关疾病的治疗。