Early neonatal treatment and immune quiescence

描述（由申请人提供）：静息CD 4记忆细胞和其他解剖学庇护所中的持久病毒库要求抗逆转录病毒治疗（ART）终身持续。最近有报道称，密西西比的一名婴儿在30岁内开始接受治疗， 婴儿出生后几个小时内，并且在不接受治疗的情况下能够维持病毒抑制，这提出了一种诱人的可能性，即在某些婴儿中建立病毒库可能是可以避免的。 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，在更多的婴儿中复制密西西比病例。我们的试验旨在测试出生后48小时内开始ART是否有可能使大多数HIV感染婴儿安全地停止ART而不会出现病毒反弹。在出生后数小时内开始ART并在18个月后停止它的背景提供了一个前所未有的机会来阐明病毒库的建立和维持所涉及的机制。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，以研究驱动病毒库建立的潜在机制。根据密西西比儿童令人兴奋的新发现，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。在出生时进行抗逆转录病毒治疗不仅在时间上接近感染， 在免疫系统向其成熟形式过渡并且处于其最静止的发育关键时期期间给予。我们还将招募一个精心挑选的4-12周龄婴儿观察队列，以常规临床服务的标准方式开始和继续ART。我们将研究当ART在年轻时开始时，T细胞上较少的CCR 5和CD 2表达，较小的CD 4记忆细胞库，减少的T细胞活化标志物，以及相对于Th 17细胞较大比例的调节性（抑制性）T细胞（T-T细胞）是否与更有限的接种和更大的病毒库衰减相关。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HIV特异性参数的非侵入性方法。

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.