Project 1: Origin and Predictors of Viral Rebound in Infants

项目 1：婴儿病毒反弹的起源和预测因素

• 批准号: 9319889
• 负责人: Ann M Chahroudi
• 金额: $ 17.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319889
• 关键词: Active Immunization; Anatomy; Animal Model; Animals; Antiviral Agents; Autopsy; Biological Markers; Breast Feeding; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Chronic; Clinical; Coculture Techniques; DNA biosynthesis; Data; Diagnosis; Disease remission; Ethical Issues; Evaluation; Gastrointestinal tract structure; Gene Expression; Genetic Variation; Genome; Goals; HIV; HIV Infections; Human Milk; Immune; Immune response; Immunologic Markers; Immunologics; Individual; Infant; Infection; Interruption; Intervention; Kinetics; Longevity; Macaca; Macaca mulatta; Measurement; Measures; Modeling; Monkeys; Morbidity - disease rate; Natural Killer Cells; Oral; Outcome; Participant; Passive Immunization; Pharmaceutical Preparations; Phylogenetic Analysis; Population; RNA; Research Personnel; Residual state; Route; Site; Source; Time; Tissues; Universities; Variant; Viral Genome; Viral Load result; Viral reservoir; Viremia; Virus; Work; age group; antiretroviral therapy; biomarker identification; design; exhaustion; experience; immune activation; insight; lymph nodes; mathematical model; mortality; next generation sequencing; nonhuman primate; novel; patient population; postnatal; predictive marker; programs; simian human immunodeficiency virus; transmission process; viral rebound; virology; virus genetics

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.

摘要-项目1(负责人：埃默里大学Ann Chahroudi博士) 在世界范围内，目前有180万儿童感染艾滋病毒，每年约有15万儿童感染艾滋病毒 其中约一半是由于母乳喂养期间的艾滋病毒传播造成的。虽然抗逆转录病毒 治疗(ART)极大地降低了艾滋病毒感染的死亡率和发病率，如果ART 被打断了。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 这种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 减刑。考虑到感染艾滋病毒的事实，在感染婴儿中诱导艾滋病毒缓解是一个非常受欢迎的结果 目前，婴儿从确诊之时起就必须在整个一生中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 在高度相关的动物模型中母乳传播。项目1的目标是i)确定 导致治疗后反弹的婴儿持续病毒库的解剖学来源 中断，以及ii)确定预测病毒反弹时间的病毒学和免疫学生物标志物 婴儿。中心假说是，受希沃克病毒感染的猕猴体内的病毒反弹源自 胃肠道和/或相关淋巴结中的CD4+T细胞亚群及其相关生物标志物 可作为病毒反弹动力学的替代指标。这项提议的一个关键特点是，通过使用 我们的新奇的高度相关的SIV感染动物模型和ART治疗，我们能够深入进行 对病毒库和治疗中断的分析是不可能在儿科进行的 参与者。项目1有以下具体目标：1)确定病毒的动力学和解剖来源 SHIV口服感染动物模型的反弹；2)鉴定细胞内病毒变异的特征序列 和ART上的解剖储存库，导致我们的治疗中断后的反跳性病毒血症 动物模型；以及3)确定预测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。该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， 并因此将有助于该方案的目标，即为制定战略提供信息，以诱导长期缓解 出生后感染的婴儿。我们希望本项目和整个计划的结果能够 向儿科人群中的艾滋病毒治疗工作提供信息。