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

描述（由申请人提供）：在获得有效的抗逆转录病毒联合治疗（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（一致性称为hiv相关神经认知障碍[HAND]）。虽然使用抗逆转录病毒治疗降低了脑病的发病率，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。该研究将应用最先进的外显子组测序技术来确定与儿童HAND相关的宿主遗传因素。本建议的具体目的是：目的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相关的新的候选遗传变异。在这个目标中，WES将用于识别与儿童HAND相关的新基因位点变异和途径。要验证的假设是，通过检查500名艾滋病毒感染儿童除HLA和杀伤igg样受体（KIR）等位基因外的所有蛋白质编码序列（外显子组），这些儿童平均分为HAND受试者和正常神经认知和神经发育功能基因位点变异的受试者，将确定与中枢神经系统疾病相关的基因位点变异。目标2：评估遗传变异与美国hiv感染儿童复制队列中中枢神经系统疾病的相关性。在目标1中发现了与HAND相关的新遗传变异，在发现队列中，约500个变异与特异性HLA/KIR基因型的相关性最高，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相关性测试。将进行特异性HLA和KIR snp的靶向外显子组测序和基因分型。目的3：检查目的1和2中鉴定的与美国儿童中枢神经系统疾病相关的遗传变异，以了解这些多态性与南非hiv感染儿童队列中中枢神经系统疾病的关联。有待验证的假设是，尽管在南非出生的一组儿童与在美国出生的儿童有很大不同，但携带变异基因的基因可以改变在美国出生的儿童患艾滋病相关中枢神经系统疾病的风险，这也将是南非出生的儿童患艾滋病风险的重要决定因素。对于这些研究，靶向外显子组测序和特定的HLA和KIR基因型将应用于南非艾滋病毒感染儿童，这些儿童接受了广泛的神经心理测量和发育测试。据我们所知，我们的研究已经获得了世界上最大的具有良好特征的具有中枢神经系统结果的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。这项研究的发现将为HAND的发病机制提供新的见解，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. PUBLIC HEALTH RELEVANCE: Despite the availability of effective antiretroviral treatment, HIV-associated Neurocognitive Disorders (HAND) is still common among HIV-infected children and adults, and the neuropathogenesis of the 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 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.