Project 1: Origin and Predictors of Viral Rebound in Infants

摘要-项目1（负责人：Ann Chahroudi博士，埃默里大学） 目前，全世界有180万儿童感染艾滋病毒，每年约有150，000例新的儿科感染。 其中约一半是由于母乳喂养期间的艾滋病毒传播而发生的。虽然抗逆转录病毒药物 抗逆转录病毒疗法（ART）大大降低了艾滋病毒感染的死亡率和发病率，如果ART是 打断了解HIV反弹的病毒学和免疫学驱动因素并确定生物标志物 预测反弹对于设计和评估旨在实现艾滋病毒的干预措施至关重要， 缓解。鉴于感染婴儿的艾滋病病毒感染率很高， 目前，婴儿从诊断时起必须在其整个生命期内每天接受抗逆转录病毒治疗。 本计划项目申请的总体目标是调查出生后环境中的病毒反弹 母乳传播在高度相关的动物模型。项目1的目标是：i）确定 导致治疗后反弹的婴儿持续性病毒储库的解剖学来源 中断，和ii）鉴定预测病毒反弹时间的病毒学和免疫学生物标志物， 婴儿。核心假设是，在SHIV感染的恒河猴幼崽中病毒反弹源于 胃肠道和/或相关淋巴结中的CD 4 + T细胞亚群以及ART期间的生物标志物 可用作病毒反弹动力学的替代指标。该提案的一个主要特点是，通过使用 我们的新的，高度相关的动物模型的SHIV感染和ART治疗，我们能够进行深入研究， 分析病毒储库和治疗中断，这在儿科中不可能进行 参与者项目1的具体目标如下：1）确定病毒的动力学和解剖起源 2）为了鉴定细胞内病毒变异体的特征序列， 在我们的研究中，ART上的解剖学储库导致治疗中断后病毒血症反弹。 动物模型;和3）鉴定预测在感染后病毒反弹时间的病毒学和免疫学生物标志物。 我们的动物模型本项目将通过与所有其他计划组成部分的互动来实现这些目标， 因此，将有助于该计划的目标，通知战略的设计，以诱导长期缓解， 出生后感染的婴儿我们希望这个项目和整个项目的研究结果能够 为儿科人群的艾滋病毒治疗工作提供信息。

ABSTRACT – Project 1 (Leader: Dr. Ann Chahroudi, Emory University) Worldwide, there are currently 1.8 million children living with HIV and ~150,000 new pediatric infections per year, approximately half of which occur due to HIV transmission during breastfeeding. While antiretroviral therapy (ART) greatly reduces mortality and morbidity of HIV infection, viral rebound quickly ensues if ART is interrupted. Understanding the virologic and immunologic drivers of HIV rebound and identifying biomarkers that predict rebound is essential for the design and evaluation of interventions that aim to achieve HIV remission. Inducing HIV remission in infected infants is a highly sought-after outcome, given the fact infected infants currently must remain on daily ART from the time of diagnosis through their entire life span. The overall goal of this Program project application is to investigate virus rebound in the setting of postnatal breast milk transmission in a highly relevant animal model. The objectives of Project 1 are i) to determine the anatomic sources of the persistent virus reservoir in infants that contribute to rebound following treatment interruption, and ii) to identify virologic and immunologic biomarkers that predict the time to virus rebound in infants. The central hypothesis is that virus rebound in SHIV-infected infant rhesus macaques originates from CD4+ T cell subsets in the gastrointestinal tract and/or associated lymph nodes and that on-ART biomarkers can be used as a surrogate indicator of virus rebound kinetics. A key feature of this proposal is that, by using our novel, highly relevant animal model of SHIV infection and ART treatment, we are able to perform in-depth analyses of virus reservoirs and treatment interruption that would be impossible to conduct in pediatric participants. Project 1 has the following Specific Aims: 1) To define the kinetics and anatomic origin of virus rebound in orally SHIV-infected animal model; 2) To identify signature sequences of virus variants in cellular and anatomic reservoirs on ART that contribute to rebound viremia following treatment interruption in our animal model; and 3) To identify virologic and immunologic biomarkers that predict the time to virus rebound in our animal model. This Project will achieve these Aims through interaction with all other Program components, and thus will contribute to the Program's goal to inform design of strategies to induce prolonged remission in postnatally infected infants. We expect the findings from this Project and the Program as a whole to critically inform HIV cure efforts in the pediatric population.