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

描述（由申请方提供）：在有效的联合抗逆转录病毒治疗（ART）可用之前，30-50%的围产期感染儿童发生严重发育迟缓、认知障碍和脑病（一致性称为HIV相关神经认知障碍[HAND]）。虽然抗逆转录病毒疗法降低了脑病的发病率，但在15-20%的艾滋病毒感染儿童中仍然发现了严重的认知障碍。此外，尽管对HAND进行了大量研究，但CNS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确定与儿童HAND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鉴定与HAND相关的新候选遗传变异。在这一目标中，WES将用于识别与儿童HAND相关的新的遗传位点变异和途径。待检验的假设是，通过检查500名HIV感染儿童中除HLA和杀伤Ig样受体（KIR）等位基因外的所有蛋白质编码序列（外显子组），将鉴定出与CNS疾病相关的基因座变体，其中500名HIV感染儿童平均分为HAND受试者和神经认知和神经发育功能正常的受试者。目标二：在美国HIV感染儿童的复制队列中评估遗传变异与CNS疾病的相关性。在Aim 1中鉴定出与HAND相关的新型遗传变异后，约500种变体与特定HLA/将在两个美国重复队列中检测发现队列中最高显著性的KIR基因型的相关性，这两个美国重复队列具有与发现队列相似的种族和社会经济背景。探索队列将对特定HLA和KIR SNP进行靶向外显子组测序和基因分型。目标3：在南非的一组HIV感染儿童中，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，以确定这些多态性与CNS疾病的相关性。有待检验的假设是，尽管在南非出生的一组儿童与在美国出生的儿童有显著差异，在美国出生的儿童中，携带变异的基因被确定为改变HIV相关CNS疾病的风险，这也将是南非儿童风险的重要决定因素。对于这些研究，有针对性的外显子组测序和特定的HLA和KIR基因型将适用于南非艾滋病毒感染的儿童谁经历了广泛的神经心理和发育测试。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。这项研究的结果将提供深入了解手的发病机制，并提出新的战略，如何治疗和预防中枢神经系统疾病与艾滋病毒。

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.