Host epigenetic and mitochondrial function in HIV-infected children

描述（由申请人提供）：围产期艾滋病毒感染儿童提供了一个独特的模型系统，以研究与艾滋病毒一起成长的慢性影响。我们建议在南非约翰内斯堡的两个治疗中心重新招募500名5-9岁的艾滋病毒感染儿童。这些儿童是临床研究的先前参与者，在生命的头两年开始接受治疗，并有详细的临床资料、与艾滋病毒有关的实验室结果和储存在储存库中的10 000多份血液标本。我们将前瞻性地随访重新入组的儿童，并收集关于合并症、毒性和并发症的标准化临床数据、实验室数据 关于艾滋病毒相关参数和血液样本以及其他用于特殊研究的标本。我们还将招募250名未感染儿童（家庭/兄弟姐妹对照）的横断面样本，这些儿童在招募时与重新招募的儿童在3个月间隔内的年龄频率匹配。我们将把新收集的随访数据和样本与历史数据库和储存库整合，以提供一个平台来研究（1）宿主表观遗传学和（2）线粒体功能及其与HIV疾病进展、药物治疗方案和HIV感染儿童代谢并发症的关系。首先，使用成熟的基于阵列的方法和焦磷酸测序，我们提出鉴定伴随围产期获得性HIV感染和HIV治疗的基因特异性DNA甲基化变化的谱。其次，利用储存和新收集的标本，我们建议测试线粒体功能障碍（通过酶功能和细胞应激的新方法测量）是否会加剧慢性炎症和免疫衰老，这些炎症和免疫衰老是HIV疾病进展和可能伴随长期治疗的代谢并发症的基础。我们的前瞻性队列，建立在广泛和良好的围产期感染人群，将提供一个宝贵的资源，进行这些和未来的发病机制为导向的研究，以告知补充干预措施的发展，以改善艾滋病毒感染的儿童在撒哈拉以南非洲的长期结果。 公共卫生相关性：我们将把联合收割机从现在的学龄期围产期HIV感染儿童中新收集的前瞻性数据与从治疗开始时前瞻性收集的临床和储存库数据结合起来。该队列将提供一个平台来研究宿主表观遗传学和线粒体功能在HIV进展和长期治疗的HIV感染的代谢并发症中的作用。

DESCRIPTION (provided by applicant): Perinatally HIV-infected children provide a unique model system to study the chronic effects of growing up with HIV. We propose to re-enroll 500 HIV-infected children age 5-9 years at two treatment sites in Johannesburg, South Africa. These children are prior participants in clinical studies who initiated therapy during the first two year of life and have detailed clinical information, HIV-related laboratory results and over 10,000 blood specimens stored in repositories. We will prospectively follow the re-enrolled children and collect standardized clinical data on co-morbidities, toxicities and complications, laboratory data on HIV-related parameters and blood samples and other specimens for special studies. We will also enroll a cross-sectional sample of 250 uninfected children (household/sibling controls) frequency-matched by age within 3-month intervals to the re- enrolled children at the time of recruitment. We will integrate the newly-collected, follow-up data and samples with the historical databases and repositories to provide a platform to investigate (1) host epigenetics and (2) mitochondrial function and their relations with HIV disease progression, drug regimens, and metabolic complications in HIV-infected children. First, using well-established array-based methods and pyrosequencing, we propose to identify the spectrum of gene-specific DNA methylation changes that accompany perinatally- acquired HIV infection and HIV treatment. Second, utilizing both stored and newly-collected specimens, we propose to test whether mitochondrial dysfunction (as measured by novel methods of enzyme function and cell stress) exacerbates chronic inflammation and immune senescence underlying HIV disease progression and the metabolic complications that may accompany long-term treatment. Our prospective cohort, building on an extensive and well-characterized perinatally-infected population, will provide a valuable resource to undertake these and future pathogenesis-oriented studies to inform development of complementary interventions to improve long-term outcomes of HIV-infected children in sub-Saharan Africa. PUBLIC HEALTH RELEVANCE: We will combine newly-collected prospective data from perinatally HIV-infected children now of school-age with already collected clinical and repository data collected prospectively from the time of treatment initiation. The cohort will provide a platform to study the role of host epigenetics and mitochondrial function in HIV progression and metabolic complications of long-term, treated HIV infection.