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）：在艾滋病毒感染功能和胸腺产量的潜在储层表征和胸腺输出与艾滋病毒感染的儿童相关性和胸腺量的相关性，鉴于南非儿童的早期抗逆转录病毒治疗，这些儿童参加了此应用程序的主要人群中的HIV早期抗逆转录病毒（CHER）试验的儿童。 CHER试验在2005年6月至2011年9月之间在开普敦（1/3）和索韦托（2/3）进行。在这项研究中，根据2006年初级艺术指南（ART-DEF），或ART 40（ART-40-40-40-40-40周），在7周龄的7周龄中，在7周龄的7周龄中随机分组了377名婴儿，以延迟抗逆转录病毒疗法（ART）。此后，艺术被停用，直到标准（CD4 <20％或CDC阶段C或严重B期B）用于重新发射艺术。在整个CHER研究中，每3个月收集每3个月收集外周血单核细胞（PBMC），并存储在液氮中。在Art-Def中，开始艺术的中位年龄为6个月。在开普敦，由于已经患有CDC C或严重的B疾病，在80名儿童中，有80名儿童中有24名没有中断，因此从7周龄开始就进行了连续艺术。来自开普敦的孩子参加了神经发育子研究，现在正在进行一项正在进行的研究，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试验中的样品，使用储存的PBMC进行了胸腺流出（TREC等）以及HIV储层的研究。对于储层研究，正在使用用于HIV长时间重复序列（LTR）（圆形和线性）的PCR。这项研究将解决所有血浆HIV RNA低于400份/mm3的血浆HIV RNA的研究出口时的总储层大小（WEK 240），并且每个研究部门的20名儿童的储层大小；在第96、150和200周的Art-Def中；在第40周的ART-40W中，在第200周重新启动ART和第200周的ART-96W中，在96周，重新启动艺术和200周。通过此应用，我们计划对开普敦Cher 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已经7岁了，因此我们计划进一步的研究，以进一步表征储层，能够安全地收集更大的Bloo量以进行感染性测定，并表征储层会随着时间的推移而衰减。我们将将储藏量与神经认知/神经成像结果和胸腺流出相关联。将在生命的第一周内在ART中发起的新的艾滋病毒感染的婴儿队列。我们的目标是每年招募12名受试者，并将将这些婴儿的水库大小与雪儿受试者的结果进行比较，而雪儿受试者的成绩是开始的7周龄。随着治疗议程的扩展和新的方式清除HIV储层变得可行，我们的同类将有很好的介入研究。

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