Early neonatal treatment and immune quiescence

新生儿早期治疗和免疫静止

基本信息

批准号：
8727251
负责人：
Louise Kuhn
金额：
$ 93.97万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727251
关键词：
Adult Age Anatomy Anti-Retroviral Agents Antibody Formation Automobile Driving Birth Blood Blood specimen CCR5 gene Caring Case Study Cells Child Chronic Clinical Clinical Services Clinical Trials Color Data Development Diagnostic tests Early treatment Eligibility Determination Event Feces Flow Cytometry Gastrointestinal tract structure HIV HIV Antibodies HIV Seropositivity Hospitals Hour Human Human immunodeficiency virus test Immune Immune system Immunity Infant Infection Intervention Intestines Laboratories Life Maintenance Measures Memory Methods Mississippi Monitor Mothers Neonatal Newborn Infant Outcome Parents Pediatric Hospitals Pharmaceutical Preparations Phenotype Population Positioning Attribute Process Public Health Quality of life Recruitment Activity Regimen Relative (related person)Reporting Research Infrastructure Rest Role Safety Sampling Schedule Services Site South Africa T-Cell Activation T-Lymphocyte Testing Time Tissues Viral antiretroviral therapy arm base clinical care cohort design functional outcomes improved infant outcome inflammatory marker innovation meetings peripheral blood point of care programs public health relevance success transmission process

项目摘要

DESCRIPTION (provided by applicant): The long-lasting viral reservoir in resting CD4 memory cells and other anatomic sanctuaries requires that antiretroviral therapy (ART) be continued life-long. The recent report of the infant in Mississippi who started treatment within 30 hours of birth and who has been able to maintain viral suppression off treatment raises the tantalizing possibility that establishment of the viral reservoir may be avoidable in some infants. Limitations of this single case report necessitate urgent replication as the potential public healt benefits of the intervention are profound. We propose a single-arm clinical trial in Johannesburg, South Africa, to replicate the Mississippi case in a more robust number of infants. Our trial is designed to test whether initiation of ART within 48 hours of birth has the potential to allow the majority of HIV-infected infants to safely discontinue ART without viral rebound. The context of starting ART within hours of birth and stopping it 18 months later provides an unprecedented opportunity to elucidate mechanisms involved in the establishment and maintenance of viral reservoir. In the context of this unique trial, we will collect samples before, during and after AR cessation to investigate potential mechanisms driving the establishment of the viral reservoir. Following the exciting new findings from the Mississippi child, we hypothesize that infant immunological developmental maturity is one of the critical parameters influencing the success of early treatment. ART given at birth is not only close in time to acquisition of infection but is given during a developmentally-critical time period when the immune system is transitioning to its mature form and is at its most quiescent. We will also recruit a carefully-selected observational cohort of infants 4-12 weeks of age initiating and continuing ART in the standard way from routine clinical services. We will investigate whether lesser CCR5 and CD2 expression on T-cells, a smaller pool of CD4 memory cells, reduced markers of T-cell activation, and larger proportions of regulatory (suppressive) T-cells (T-regs) relative to Th17 cells will be associated with more limited seeding and greater decay of the viral reservoir when ART is started at a young age. We will also investigate whether markers in infant stool samples can be used as a non-invasive method of defining relevant immune and HIV-specific parameters associated with smaller viral reservoirs.

描述（由申请人提供）：静息 CD4 记忆细胞和其他解剖庇护所中的持久病毒库需要终生持续抗逆转录病毒治疗 (ART)。最近密西西比州一名婴儿在 30 天内开始接受治疗的报告出生后的几个小时以及在治疗后能够维持病毒抑制的人提出了一种诱人的可能性，即在某些婴儿中病毒库的建立是可以避免的。这一单一病例报告的局限性需要紧急复制，因为干预措施的潜在公共卫生益处是深远的。我们建议在南非约翰内斯堡进行一项单臂临床试验，以在更多的婴儿中复制密西西比州的病例。我们的试验旨在测试出生后 48 小时内开始 ART 是否有可能让大多数感染 HIV 的婴儿安全地停止 ART 而不会出现病毒反弹。在出生后数小时内开始 ART 并在 18 个月后停止的背景为阐明病毒库建立和维持所涉及的机制提供了前所未有的机会。在这项独特的试验中，我们将在 AR 停止之前、期间和之后收集样本，以研究驱动病毒储存库建立的潜在机制。根据密西西比儿童的令人兴奋的新发现，我们假设婴儿免疫发育成熟度是影响早期治疗成功的关键参数之一。出生时给予的 ART 不仅在感染发生的时间很近，而且在免疫系统正在向成熟形式过渡且处于最静止状态的发育关键时期给予。我们还将招募一组精心挑选的 4-12 周龄婴儿观察队列，以常规临床服务中的标准方式开始并继续 ART。我们将研究相对于 Th17 细胞，T 细胞上的 CCR5 和 CD2 表达是否较少、CD4 记忆细胞库是否较小、T 细胞激活标记物是否减少以及调节性（抑制性）T 细胞 (T-regs) 比例是否较高当在年轻时开始抗逆转录病毒疗法时，将导致播种更加有限和病毒库的更大衰退有关。我们还将研究婴儿粪便样本中的标记物是否可以用作定义与较小病毒库相关的相关免疫和艾滋病毒特异性参数的非侵入性方法。