Lipidome composition, immune activation and subclinical vascular disease in Adolescents with perinatally acquired HIV in Uganda

乌干达围产期感染 HIV 的青少年的脂质组成、免疫激活和亚临床血管疾病

• 批准号: 10455682
• 负责人: Sahera Dirajlal-Fargo
• 金额: $ 19.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455682
• 关键词: Adolescence; Adolescent; Adult; Age; Anti-Retroviral Agents; Area; Biological; Biological Markers; Biological Specimen Banks; Cardiovascular Diseases; Cardiovascular system; Categories; Ceramides; Child; Childhood; Cholesterol; Cholesterol Esters; Clinical Research; Cohort Studies; Data; Disease; Eastern Africa; Enrollment; Exposure to; FarGo; Fatty Acids; Goals; HIV; HIV Infections; HIV Seronegativity; Individual; Inflammation; Inflammatory; Insulin Resistance; Intervention; Joints; Knowledge; Lipids; Longitudinal Studies; Measures; Metabolic; Outcome; Pathway interactions; Perinatal; Persons; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Plasma; Population; Recording of previous events; Research Infrastructure; Risk; Role; Signal Transduction; Southern Africa; Surrogate Markers; Testing; Time; Uganda; Validation; Vascular Diseases; Viral; Virus Replication; Youth; antiretroviral therapy; biomarker signature; cardiometabolism; carotid intima-media thickness; clinical prognostic; cohort; comorbidity; comparison group; immune activation; improved; innovation; insight; intimal medial thickening; lipidome; lipidomics; longitudinal design; low and middle-income countries; novel; novel marker; prenatal exposure; prevent; prospective; screening; sex; systemic inflammatory response

Project Summary/Abstract: There are 2.1 million children under 15 years living with HIV worldwide; the vast majority have perinatally acquired HIV (PHIV) and reside in Eastern and Southern Africa. Children living with PHIV are now expected to live through adolescence and well into adulthood, such that adolescents now represent the largest growing population living with HIV. Several comorbidities, including cardiometabolic, have been associated with heightened immune activation and inflammation despite viral suppression in adults living with HIV. Because of the small size and paucity of pediatric data, controversy exists regarding the mechanisms and the extent to which heightened inflammation should be concerning in this young population during formative years. Lipidomics analyses have revealed associations of lipid classes and fatty acid composition with inflammation and several diseases, including cardiometabolic complications. The overall goal of this project is to obtain new insight into PHIV and the factors associated with immune activation and subclinical cardiovascular disease. We will use novel unbiased analysis of integrated lipidomic and bring an innovative approach to identify signaling cascades related to lipid processing that may predict cardiovascular complications in PHIV. In a longitudinal study of 100 PHIV and age-and sex-matched uninfected controls, this project aims to measure the lipidome over 96 weeks to identify lipid perturbations associated with HIV and pathways associated with immune activation. We will investigate whether pro- inflammatory lipids are predictive of subclinical vascular disease. Additionally, we will examine the role of specific ART classes as well as individual antiretroviral drugs on the lipidome. The proposed study leverages the rich data of Dr. Dirajlal-Fargo’s K23 study in Uganda. This study will build on the well-phenotyped cohort of virally suppressed adolescents with PHIV and age-and sex- matched uninfected comparison group and utilize repository specimens. The longitudinal design will allow for data validation and replication, a major criticism of prior observational omics studies. This study may reveal novel biomarker signatures of biological, clinical, and prognostic relevance to prevent cardiovascular disease for adolescents who are advancing into adulthood and have received long-term ART.

项目摘要/摘要： 全球有 210 万 15 岁以下儿童感染艾滋病毒； 围产期感染艾滋病毒 (PHIV) 并居住在东部和南部非洲的儿童。 现在预计感染了 PHIV 的人会度过青春期并进入成年期，因此 青少年现在是感染艾滋病毒的人数最多的群体，有几种合并症， 包括心脏代谢，与哮喘免疫激活有关 尽管艾滋病病毒感染者的病毒受到抑制，但仍会出现炎症，因为其体积小且体积小。 由于缺乏儿科数据，关于其机制和程度存在争议 对于处于成长阶段的年轻人来说，恶性炎症应该引起关注。 脂质组学分析揭示了脂质类别和脂肪酸的关联 与炎症和多种疾病（包括心脏代谢并发症）有关的成分。 该项目的总体目标是获得对 PHIV 及其相关因素的新见解 我们将使用新型公正的免疫激活和亚临床心血管疾病。 综合脂质组学分析并带来识别信号传导的创新方法 与脂质加工相关的级联反应可以预测心血管并发症 在一项针对 100 名 PHIV 以及年龄和性别匹配的未感染者的纵向研究中， 该项目旨在测量 96 周内的脂质组，以确定相关的脂质扰动 我们将研究是否与 HIV 相关以及与免疫激活相关的途径。 此外，炎症性脂质可以预测亚临床血管疾病。 特定 ART 类别以及单个抗逆转录病毒药物对脂质组的作用。 拟议的研究利用了 Dirajlal-Fargo 博士在乌干达进行的 K23 研究的丰富数据。 这项研究将建立在病毒抑制的 PHIV 青少年表型良好的队列基础上 和年龄和性别匹配的未感染对照组并利用储存库标本。 纵向设计将允许数据验证和复制，这是对 先前的观察组学研究可能揭示新的生物标志物特征。 预防青少年心血管疾病的生物学、临床和预后相关性 即将进入成年并接受长期抗逆转录病毒治疗的人。