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: 10170232
• 负责人: Sulggi Angela Lee
• 金额: $ 80.45万
• 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/10170232
• 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.

项目摘要/摘要