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: 9513619
• 负责人: Mark Fredric Cotton
• 金额: $ 57.18万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513619
• 关键词: 11 year old; 12 year old; 5 year old; 7 year old; Address; Age; Age-Months; 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; 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; recruit; 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感染儿童中，潜伏库特征及其与12年以上神经认知功能和胸腺输出的相关性参与开普敦HIV早期抗逆转录病毒（CHER）试验的儿童是该应用的主要人群。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周龄以下的婴儿根据2006年指南（ART- def）按中位数7周龄随机接受延迟抗逆转录病毒治疗（ART），或立即接受初级ART治疗，直至第40周（ART- 40w）或第96周（ART- 96w）。此后，抗逆转录病毒治疗停止，直到制定了重新启动抗逆转录病毒治疗的标准（CD4 <20%或CDC C期或严重B期）。在整个CHER研究过程中，每3个月收集外周血单个核细胞（PBMCs）并保存在液氮中。在ART- def中，开始ART治疗的中位年龄为6个月。在开普敦，80名随机接受早期抗逆转录病毒治疗的儿童中有24名没有因为已经患有CDC C或严重的B期疾病而中断治疗，因此从7周龄开始持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亚研究，现在正在参与一项正在进行的研究，该研究描述了未来3年的神经认知功能和神经放射学结果。使用两个研究地点储存的CHER试验样本，胸腺流出物（TREC等）和HIV库的研究正在使用储存的pbmc进行。对于储库研究，正在使用HIV长末端重复序列（LTR）的PCR（圆形和线性）。本研究将研究所有血浆HIV RNA低于400拷贝/mm3的儿童在研究结束时（第240周）的总库大小，以及来自每个研究组的20名儿童的库大小；ART-Def第96、150和200周；ART- 40w在第40周，重新启动ART和第200周，ART- 96w在第96周，重新启动ART和第200周。通过该应用程序，我们计划对开普敦CHER患者早期储存的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，以进一步表征储层，能够安全地收集更大的血容量进行感染性分析，并表征储层如何随时间衰减。在我们的队列中，我们将把储液池的大小与神经认知/神经影像学结果和胸腺流出量联系起来。还将研究一组在出生后第一周内开始接受抗逆转录病毒治疗的艾滋病毒感染婴儿。我们的目标是每年招募12名受试者，并将这些婴儿的储存库大小与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HIV病毒库的新模式变得可行，我们的队列将很好地进行介入性研究。

项目成果

Rapid decline of HIV-1 DNA and RNA in infants starting very early antiretroviral therapy may pose a diagnostic challenge.

• DOI: 10.1097/qad.0000000000001739
• 发表时间: 2018-03-13
• 期刊: AIDS (London, England)
• 作者: Veldsman KA;Maritz J;Isaacs S;Katusiime MG;Janse van Rensburg A;Laughton B;Mellors JW;Cotton MF;van Zyl GU
• 通讯作者: van Zyl GU

Viral suppression is associated with HIV-antibody level and HIV-1 DNA detectability in early treated children at 2 years of age.

• DOI: 10.1097/qad.0000000000002861
• 发表时间: 2021-07-01
• 期刊: AIDS (London, England)
• 作者: Veldsman KA;Laughton B;Janse van Rensburg A;Zuidewind P;Dobbels E;Barnabas S;Fry S;Cotton MF;van Zyl GU
• 通讯作者: van Zyl GU

Early Emergence and Long-Term Persistence of HIV-Infected T-Cell Clones in Children.

• DOI: 10.1128/mbio.00568-21
• 发表时间: 2021-04-08
• 期刊: mBio
• 影响因子: 6.4
• 作者: Bale MJ;Katusiime MG;Wells D;Wu X;Spindler J;Halvas EK;Cyktor JC;Wiegand A;Shao W;Cotton MF;Hughes SH;Mellors JW;Coffin JM;Van Zyl GU;Kearney MF
• 通讯作者: Kearney MF