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

描述(由申请人提供)：在获得有效的联合抗逆转录病毒疗法(ART)之前，30%-50%的围产期感染儿童发生了严重的发育迟缓、认知障碍和脑病(一致称为艾滋病毒相关神经认知障碍[HAND])。虽然抗逆转录病毒疗法降低了脑病的发生率，但仍有15%-20%的艾滋病毒感染儿童存在严重的认知障碍。此外，尽管目前已经进行了大量的研究，但中枢神经系统损伤的神经发病机制仍有待阐明。这项研究将应用最先进的外显子组测序技术来识别与儿童手相关的宿主遗传因素。这项建议的具体目标是：目标1：应用完整外显子组测序(WES)在发现的围产期感染儿童队列中识别与HAND相关的新的候选遗传变异。在这一目标中，WES将被用来识别与儿童手相关的新的遗传位点变异和途径。要测试的假设是，通过检查500名感染艾滋病毒的儿童中的所有蛋白质编码序列(外显子)以及人类白细胞抗原和杀伤免疫球蛋白样受体(KIR)等位基因，将手部疾病患者和神经认知和神经发育功能正常的患者平均分配，将确定与中枢神经系统疾病相关的基因位点变异。目的2：在美国HIV感染儿童的复制队列中评估基因变异与中枢神经系统疾病的相关性。在发现了与Hand in Aim 1相关的新基因变异后，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测试~500个变异与发现队列中最重要的特定HL A/KIR基因之间的关联。将对特定的人类白细胞抗原和KIR单核苷酸多态进行有针对性的外显子组测序和基因分型。目的3：检测AIMS 1和AIMS 2中发现的与美国儿童中枢神经系统疾病相关的基因变异，以确定这些多态与南非HIV感染儿童队列中中枢神经系统疾病的相关性。需要检验的假设是，尽管在南非出生的儿童与在美国出生的儿童显著不同，但携带变异基因的美国出生儿童患艾滋病毒相关中枢神经系统疾病的风险也将是南非儿童风险的重要决定因素。在这些研究中，将有针对性的外显子组测序和特定的人类白细胞抗原和KIR基因型别应用于南非感染艾滋病毒的儿童，这些儿童已经接受了广泛的神经心理测量和发育测试。据我们所知，我们的研究获得了世界上最大的具有CNS结果的特征良好的艾滋病毒感染儿童的队列，并将首次将外显子组测序应用于大量艾滋病毒感染儿童。这项研究的结果将为HAND的发病机制提供见解，并提出如何治疗和预防与HIV相关的中枢神经系统疾病的新策略。

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.