Latent reservoir characterization and correlations with neurocognitive functionin

潜在储层特征及其与神经认知功能的相关性

• 批准号: 9301032
• 负责人: Mark Fredric Cotton
• 金额: $ 57.57万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-09 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301032
• 关键词: 11 year old; 12 year old; 5 year old; 7 year old; Address; Age; Age-Months; Alpha Cell; Anti-Retroviral Agents; Biological Assay; Centers for Disease Control and Prevention (U.S.); Child; Development; Disease; Early treatment; Enrollment; Goals; Guidelines; HIV; HIV Infections; HIV Long Terminal Repeat; Immune; Immunologics; Infant; International; Intervention Studies; Kinetics; Life; Liquid substance; Measurement; Modality; Neurocognitive; Neurologic; Neurologic Effect; Nitrogen; Outcome; Output; Patients; Peripheral Blood Mononuclear Cell; Plasma; Population; Prospective Studies; RNA; Randomized; Recruitment Activity; Research; Sampling; Shapes; Site; South Africa; South African; Specimen; T-Lymphocyte; Thymus Gland; Time; Work; antiretroviral therapy; arm; cohort; infancy; neuroimaging; pediatric human immunodeficiency virus; prospective; public health relevance; purge; reconstitution; therapy development; therapy duration; virology

DESCRIPTION (provided by applicant): Latent reservoir characterization and correlations with neurocognitive functioning and thymic output over 12 years in HIV-infected children given early antiretroviral treatment in South Africa Children who participated in the Children with HIV Early Antiretroviral (CHER) Trial in Cape Town are the main population in this application. The CHER trial took place in Cape Town (1/3) and Soweto (2/3) between June 2005 and September 2011. In this study, 377 infants below 12 weeks of age were randomized at a median of 7 weeks of age to deferred antiretroviral therapy (ART) according to 2006 guidelines (ART-Def), or immediate primary ART until either Week 40 (ART-40W) or Week 96 (ART-96W). Thereafter, ART was discontinued until criteria (CD4 <20% or CDC Stage C or severe Stage B) for re-initiating ART developed. Throughout the CHER study, peripheral blood mononuclear cells (PBMCs) were collected every 3 months and stored in liquid Nitrogen. In ART-Def, median age of starting ART was 6 months. In Cape Town, 24 of 80 children randomized to early ART did not interrupt because of already having CDC C or severe Stage B disease, thus were on continuous ART from 7 weeks of age. Children from Cape Town participated in a neurodevelopmental sub-study and are now enrolled in an ongoing study describing neurocognitive functioning and neuroradiological findings for the next 3 years. Using stored samples from the CHER trial from both study sites, studies of thymic outflow (TREC etc) and also HIV reservoir are in progress using stored PBMCs. For the reservoir studies, a PCR for HIV Long Terminal Repeats (LTR) (circular and linear) is being used. This study will address total reservoir size at study exit (Wek 240) in all children with plasma HIV RNA below 400 copies/mm3 and also reservoir size in 20 children from each study arm; in ART-Def at weeks 96, 150 and 200; in ART-40W at week 40, at restarting ART and week 200 and in ART-96W at week, 96, at restarting ART and at Week 200. Through this application, we plan more detailed studies of early stored PBMC specimens from Cape Town CHER patients. As the median age of children is now 7 years of age, we plan prospective studies to further characterize the reservoir, being able to safely collect larger bloo volumes for infectivity assays and to characterize how the reservoir will decay over time. We will correlate reservoir size with neurocognitive/ neuroimaging outcome and thymic outflow in our cohort. A new cohort of HIV-infected infants initiated on ART within the first week of life will alo be studied. We aim to recruit 12 subjects per year, and will compare reservoir size in these infants with results from the CHER subjects, who were started at a median of 7 weeks of age. As the cure agenda expands and new modalities to purge the HIV reservoir become feasible, our cohort will be well placed for interventional studies.

描述(由申请人提供)：在南非接受早期抗逆转录病毒治疗的艾滋病毒感染儿童12年来的潜在宿主特征及其与神经认知功能和胸腺输出的相关性在开普敦参加艾滋病毒儿童早期抗逆转录病毒(CHER)试验的儿童是这项申请的主要人群。Cher的审判于2005年6月至2011年9月期间在开普敦(1/3)和索韦托(2/3)进行。在这项研究中，377名12周以下的婴儿被随机分组，根据2006年的指南(ART-Def)，平均7周大的婴儿接受延期抗逆转录病毒治疗(ART-Def)，或立即接受初级ART治疗，直到第40周(ART-40W)或第96周(ART-96W)。此后，ART停止，直到制定了重新启动ART的标准(CDC C期或严重B期)。在整个CHER研究中，每3个月收集一次外周血单个核细胞(PBMC)，并将其储存在液氮中。在ART-Def中，开始接受ART的中位年龄为6个月。在开普敦，随机接受早期抗逆转录病毒治疗的80名儿童中，有24名没有因为已经患有CDC C或严重的B期疾病而中断治疗，因此从7周大开始就继续接受抗逆转录病毒治疗。来自开普敦的儿童参加了一项神经发育分研究，目前正在进行的一项研究描述了未来3年的神经认知功能和神经放射学发现。使用来自两个研究地点的CHER试验的存储样本，正在使用存储的PBMC进行胸腺流出(TREC等)和HIV储存库的研究。在水库研究中，使用了HIV长末端重复序列的聚合酶链式反应(环状和线状)。这项研究将解决所有血浆HIV RNA低于400拷贝/mm3的儿童在研究出口(Wek 240)的总存储容量，以及来自每个研究组的20名儿童的存储容量；在ART-Def中，在第96、150和200周；在ART-Def中，在第40周，在重新开始ART和第200周时；在ART-96W中，在重新开始ART时和在第200周。通过这一应用，我们计划对开普敦雪人患者的早期保存的PBMC样本进行更详细的研究。由于儿童的平均年龄现在是7岁，我们计划进行前瞻性研究，以进一步描述储存库的特征，能够安全地收集更大的血量进行感染性分析，并表征储存库将如何随着时间的推移而腐烂。我们将在我们的队列中将储存库大小与神经认知/神经成像结果和胸腺流出相关。还将对在出生第一周内开始接受抗逆转录病毒治疗的新的艾滋病毒感染婴儿队列进行研究。我们的目标是每年招募12名受试者，并将这些婴儿的储罐大小与CHER受试者的结果进行比较，CHER受试者在7周大的中位数开始。随着治疗议程的扩大和清除艾滋病毒宿主的新方法变得可行，我们的队列将处于介入研究的有利地位。