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: 10194352
• 负责人: Ann M Chahroudi
• 金额: $ 25.73万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194352
• 关键词: Active Immunization; Anatomy; Animal Model; Animals; Antiviral Agents; Autopsy; Biological Markers; Breast Feeding; CD4 Positive T Lymphocytes; Cells; Child; Childhood; 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; ImmunoPET; 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; T-Lymphocyte Subsets; Time; Tissues; Universities; Variant; Viral Genome; Viral Load result; Viral reservoir; Viremia; Virus; Work; age group; antiretroviral therapy; biomarker identification; chronic infection; design; exhaustion; experience; immune activation; infant infection; 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：Ann Chahroudi 博士，埃默里大学） 全球目前有 180 万儿童感染艾滋病毒，并且每年约有 15 万新发儿科感染者 年，其中大约一半是由于母乳喂养期间艾滋病毒传播而发生的。虽然抗逆转录病毒 治疗（ART）大大降低了 HIV 感染的死亡率和发病率，如果 ART 有效，病毒很快就会反弹 打断了。了解艾滋病毒反弹的病毒学和免疫学驱动因素并识别生物标志物 预测反弹对于设计和评估旨在实现艾滋病毒目标的干预措施至关重要 缓解。鉴于感染婴儿的事实，诱导感染婴儿的艾滋病毒缓解是一个备受追捧的结果 目前，婴儿从诊断之时起直至其整个生命周期都必须每天接受抗逆转录病毒治疗。 该计划项目申请的总体目标是调查产后环境中的病毒反弹 高度相关的动物模型中的母乳传播。项目 1 的目标是 i) 确定 婴儿体内持久性病毒库的解剖来源有助于治疗后的反弹 中断，ii) 识别病毒学和免疫学生物标志物，预测病毒反弹的时间 婴儿。核心假设是，感染 SHIV 的幼年恒河猴体内的病毒反弹源自 胃肠道和/或相关淋巴结中的 CD4+ T 细胞亚群以及 ART 生物标志物 可用作病毒反弹动力学的替代指标。该提案的一个关键特点是，通过使用 我们的新型、高度相关的 SHIV 感染和 ART 治疗动物模型，我们能够进行深入的研究 对病毒储存库和治疗中断的分析在儿科中是不可能进行的 参与者。项目 1 有以下具体目标： 1) 定义病毒的动力学和解剖起源 口服 SHIV 感染动物模型中的反弹； 2) 鉴定细胞内病毒变种的特征序列 以及 ART 上的解剖学储存库，在我们的治疗中断后会导致病毒血症反弹。 动物模型； 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件的交互来实现这些目标， 从而有助于实现该计划的目标，即为诱导长期缓解的策略设计提供信息 产后感染的婴儿。我们期望该项目和整个计划的调查结果能够批判性地 为儿科人群的艾滋病毒治疗工作提供信息。