Host epigenetic and mitochondrial function in HIV-infected children

描述(由申请人提供)：围产期感染艾滋病毒的儿童提供了一个独特的模型系统来研究成长过程中感染艾滋病毒的慢性影响。我们建议在南非约翰内斯堡的两个治疗地点重新招收500名5-9岁的艾滋病毒感染儿童。这些儿童以前参加过临床研究，他们在出生的头两年开始治疗，并有详细的临床信息、与艾滋病毒有关的实验室结果和储存在储存库中的10,000多份血液样本。我们将前瞻性地跟踪重新登记的儿童，并收集有关合并症、毒性和并发症的标准化临床数据、实验室数据 对艾滋病毒相关参数和血液样本等进行专门研究。我们还将招募250名未感染病毒的儿童(家庭/兄弟姐妹对照)的横断面样本--与招募时重新登记的儿童在3个月内按年龄匹配的频率。我们将把新收集的跟踪数据和样本与历史数据库和知识库结合起来，提供一个平台来研究(1)宿主表观遗传学和(2)线粒体功能及其与艾滋病毒感染儿童疾病进展、药物方案和代谢并发症的关系。首先，使用成熟的基于阵列的方法和焦磷酸测序，我们建议识别伴随着围产期获得性艾滋病毒感染和艾滋病毒治疗的基因特异性DNA甲基化变化的频谱。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衡量)是否会加剧导致艾滋病毒疾病进展的慢性炎症和免疫衰老，以及可能伴随长期治疗而出现的代谢并发症。我们的预期队列建立在广泛和特征良好的围产期感染人群的基础上，将提供宝贵的资源，以开展这些和未来以发病机制为导向的研究，为制定补充干预措施提供信息，以改善撒哈拉以南非洲艾滋病毒感染儿童的长期结果。

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.