Host Genetic Factors Associated with CNS Disease of HIV-Infected Children

与艾滋病毒感染儿童中枢神经系统疾病相关的宿主遗传因素

基本信息

批准号：
8641735
负责人：
STEPHEN A SPECTOR
金额：
$ 69.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641735
关键词：
AIDS/HIV problem Adolescent Adult Affect African Age Alleles Anti-Retroviral Agents Central Nervous System Diseases Child Code Cognitive Cohort Studies Complication Copy Number Polymorphism Developed Countries Developing Countries Development Developmental Delay Disorders Disease Drug usage Encephalopathies Ethnic group Exons Genes Genetic Genetic Models Genetic Polymorphism Genotype HIV HIV Infections Hispanics Illicit Drugs Impaired cognition Impairment Incidence Infection Longitudinal Studies Matched Group Modeling Natural Immunity Neurocognitive Neuropathogenesis Not Hispanic or Latino Outcome Pathogenesis Pathway interactions Perinatal Proteins Protocols documentation Research Risk Risk Factors Single Nucleotide Polymorphism South Africa Subgroup Technology Testing Time Variant adaptive immunity antiretroviral therapy base cognitive function cohort exome sequencing gene function genetic variant indexing insight neuropsychiatry novel novel strategies patient population prevent receptor socioeconomics solution hybridization tool virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Severe developmental delays, cognitive impairment and encephalopathy (which for consistency are referred to as HIV-associated Neurocognitive Disorders [HAND]) occurred in 30-50% of perinatally infected children prior to the availability of effective combination antiretroviral therapy (ART). While with ART the incidence of encephalopathy has been reduced, severe cognitive impairment is still identified in 15-20% of HIV-infected children. Additionally, although much research has been performed on HAND, the neuropathogenesis of CNS impairment remains to be elucidated. The research proposed will apply state-of-the-art exome sequencing technology to identify the host genetic factors associated with HAND in children. The specific aims of this proposal are: Aim 1: Apply whole exome sequencing (WES) to identify novel candidate genetic variants associated with HAND in a discovery cohort of perinatally infected children. In this aim, WES will be used to identify novel genetic locus variants and pathways that are associated with HAND in children. The hypothesis to be tested is that by examining all protein-coding sequences (exomes) in addition to HLA and killer Ig-like receptor (KIR) alleles in 500 HIV-infected children equally divided between subjects with HAND and those with normal neurocognitive and neurodevelopmental function gene locus variants will be identified which are associated with CNS disease. Aim 2: Evaluate the associations of the genetic variants with CNS disease in replication cohorts of HIV-infected children in the U.S. Having identified novel genetic variants that are associated with HAND in Aim 1, the association of ~500 variants and specific HLA/KIR genotypes of highest significance in the discovery cohort will be tested for association in two U.S. replication cohorts with similar ethnic and socioeconomic backgrounds as the discovery cohort. Targeted exome sequencing and genotyping of specific HLA and KIR SNPs will be performed. Aim 3: Examine the genetic variants identified in Aims 1 and 2 associated with CNS disease of children in the U.S. for association of these polymorphisms with CNS disease in a cohort of HIV-infected children in South Africa. The hypothesis to be tested is that although a cohort of children born in South Africa differs significantly from those born in the U.S., genes carrying variants identified to alter the risk of HIV-related CNS disease in U.S. born children will also be important determinants of risk for children from South Africa. For these studies, targeted exome sequencing and specific HLA and KIR genotypes will be applied to South African HIV-infected children who have undergone extensive neuropsychometric and developmental testing. To our knowledge, our research has access to the largest cohorts of well-characterized HIV-infected children with CNS outcomes in the world, and will for the first time apply exome sequencing to large number of HIV-infected children. The findings of this research will provide insights into the pathogenesis of HAND and suggest novel strategies how to treat and to prevent the CNS disease associated with HIV.

描述（由申请人提供）：在获得有效的联合抗逆转录病毒药物之前，30-50% 的围产期感染儿童出现严重发育迟缓、认知障碍和脑病（为了保持一致性，称为 HIV 相关神经认知障碍 [HAND]）治疗（ART）。虽然通过 ART 降低了脑病的发生率，但 15-20% 的 HIV 感染儿童仍然存在严重的认知障碍。此外，尽管对 HAND 进行了大量研究，但中枢神经系统损伤的神经发病机制仍有待阐明。拟议的研究将应用最先进的外显子组测序技术来识别与儿童手部疾病相关的宿主遗传因素。该提案的具体目标是：目标 1：应用全外显子组测序 (WES) 在围产期感染儿童的发现队列中识别与 HAND 相关的新候选遗传变异。为此，WES 将用于识别与儿童 HAND 相关的新基因位点变异和途径。要测试的假设是，通过检查 500 名 HIV 感染儿童中除 HLA 和杀伤性 Ig 样受体 (KIR) 等位基因之外的所有蛋白质编码序列（外显子组），这些儿童平均分为 HAND 受试者和神经认知和神经发育正常受试者。将鉴定与中枢神经系统疾病相关的功能基因位点变异。目标 2：评估美国 HIV 感染儿童复制队列中遗传变异与中枢神经系统疾病的关联。在目标 1 中鉴定出与 HAND 相关的新遗传变异后，约 500 个变异与特定 HLA/KIR 基因型之间存在关联发现队列中最显着的特征将在两个与发现队列具有相似种族和社会经济背景的美国复制队列中进行关联性测试。将进行特定 HLA 和 KIR SNP 的靶向外显子组测序和基因分型。目标 3：检查目标 1 和 2 中确定的与美国儿童 CNS 疾病相关的遗传变异，以了解这些多态性与南非 HIV 感染儿童队列中 CNS 疾病的关联。待测试的假设是，尽管南非出生的儿童群体与美国出生的儿童群体存在显着差异，但携带变异体的基因被确定可改变美国出生儿童患艾滋病毒相关中枢神经系统疾病的风险，这也将是风险的重要决定因素。为来自南非的儿童。在这些研究中，针对性的外显子组测序以及特定的 HLA 和 KIR 基因型将应用于经过广泛的神经心理测量和发育测试的南非 HIV 感染儿童。据我们所知，我们的研究接触到了世界上最大的具有 CNS 结局的、特征明确的 HIV 感染儿童队列，并将首次将外显子组测序应用于大量 HIV 感染儿童。这项研究的结果将深入了解 HAND 的发病机制，并提出治疗和预防与 HIV 相关的中枢神经系统疾病的新策略。