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 HIV 感染儿童 12 年来的潜伏病毒库特征及其与神经认知功能和胸腺输出的相关性 参加开普敦 HIV 儿童早期抗逆转录病毒 (CHER) 试验的儿童是本申请的主要人群。 CHER 试验于 2005 年 6 月至 2011 年 9 月在开普敦 (1/3) 和索韦托 (2/3) 进行。在这项研究中，377 名 12 周以下的婴儿在中位 7 周龄时被随机分配到根据 2006 年指南 (ART-Def) 进行延迟抗逆转录病毒治疗 (ART)，或立即进行初级 ART 直至第 40 周 (ART-40W) 或第 96 周（ART-96W）。此后，停止 ART 直至达到重新开始 ART 的标准（CD4 <20% 或 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核细胞 (PBMC) 并储存在液氮中。在 ART-Def 中，开始 ART 的中位年龄为 6 个月。在开普敦，80 名随机接受早期 ART 的儿童中有 24 名没有因为已经患有 CDC C 或严重的 B 期疾病而中断，因此从 7 周龄开始持续接受 ART。来自开普敦的儿童参加了一项神经发育子研究，现在正在参加一项正在进行的研究，该研究描述未来 3 年的神经认知功能和神经放射学发现。使用来自两个研究中心的 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。对于储存库研究，正在使用 HIV 长末端重复序列 (LTR)（环状和线性）的 PCR。这项研究将探讨研究结束时（第 240 周）血浆 HIV RNA 低于 400 拷贝/mm3 的所有儿童的总水库大小，以及每个研究组 20 名儿童的水库大小；在 ART-Def 中第 96、150 和 200 周；在 ART-40W 中，第 40 周，重新启动 ART 时和第 200 周；在 ART-96W 中，在第 96 周，重新启动 ART 时和第 200 周。通过此应用程序，我们计划对来自开普敦 CHER 患者的早期存储的 PBMC 标本进行更详细的研究。由于儿童的中位年龄现在为 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液量进行感染性测定，并描述储存库如何随着时间的推移而衰减。我们将把储存库大小与我们队列中的神经认知/神经影像结果和胸腺流出相关联。还将对在出生后第一周内开始接受抗逆转录病毒治疗的一组新的艾滋病毒感染婴儿进行研究。我们的目标是每年招募 12 名受试者，并将这些婴儿的水库大小与 CHER 受试者的结果进行比较，CHER 受试者的中位年龄为 7 周龄。随着治疗议程的扩大和清除艾滋病毒储存库的新方法变得可行，我们的队列将为介入研究做好准备。