Early neonatal treatment and immune quiescence

描述(申请人提供)：在静止的CD4记忆细胞和其他解剖避难所中的长期病毒储存库要求抗逆转录病毒治疗(ART)持续终生。最近密西西比州的一名婴儿在30岁内开始接受治疗 出生几个小时后，以及在治疗期间能够保持病毒抑制的人，增加了一种诱人的可能性，即在一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，因为干预措施对公众健康的潜在好处是深远的。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州的病例。我们的试验旨在测试在出生后48小时内开始抗逆转录病毒疗法是否有可能允许大多数感染艾滋病毒的婴儿安全地停止抗逆转录病毒疗法，而不会出现病毒反弹。在出生后数小时内启动ART并在18个月后停止ART的背景为阐明建立和维持病毒库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，以调查推动病毒库建立的潜在机制。根据密西西比州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。出生时给予的抗逆转录病毒治疗不仅在感染时间上接近，而且在 在发育关键时期给药，此时免疫系统正向成熟状态过渡，处于最静止状态。我们还将招募精心挑选的4-12周婴儿观察队列，以常规临床服务的标准方式开始和继续抗逆转录病毒治疗。我们将研究T细胞上较少的CCR5和CD2表达，较小的CD4记忆细胞池，较少的T细胞激活标记，以及相对于Th17细胞较大比例的调节(抑制)T细胞(T-regs)是否与在年轻时开始抗逆转录病毒治疗时更有限的播种和更大的病毒库腐烂有关。我们还将调查婴儿粪便样本中的标志物是否可以作为一种非侵入性方法来确定与较小病毒库相关的免疫和艾滋病毒特异性参数。

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.