PROBING the DYNAMICS of INFANT IMMUNITY to LIMIT HIV PERSISTENCE

探索婴儿免疫力的动态以限制艾滋病毒的持续存在

基本信息

批准号：
9538578
负责人：
Nancy L Haigwood
金额：
$ 81.91万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-03 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9538578
关键词：
Acute Adaptive Immune System Address Adolescent Adult Affect Animal Model Animals Attenuated Autopsy B-Lymphocyte Subsets B-Lymphocytes Biological Markers Birth Blood Breast Feeding CD4 Positive T Lymphocytes Cell Compartmentation Cell physiology Cells Cessation of life Characteristics Child Childhood Clinical Clinical Data Complement Data Development Disease Disease Progression Disease remission Early treatment Evaluation Foundations Funding Future Goals HIV HIV Infections HIV-1 Human Humoral Immunities Image Immune Immune System Diseases Immune response Immune system Immunity Immunologics Immunotherapy Incidence Infant Infection Intervention Kinetics Knowledge Life Lymphoid Lymphoid Tissue Macaca Macaca mulatta Methodology Modeling Molecular Morbidity - disease rate Multimodal Imaging Natural Immunity Newborn Infant Oral Oregon Outcome Pathogenesis Pathway interactions Perinatal Perinatal Infection Pharmacotherapy Plasma Positron-Emission Tomography Postpartum Period Pre-Clinical Model Pregnancy Prevention strategy Primates Publishing Reagent Research Research Personnel Risk Route Sampling T-Lymphocyte Time Tissues Umbilical Cord Blood United States National Institutes of Health Viral Viral reservoir Viremia Virus Virus Latency Virus Replication Work adaptive immune response adaptive immunity base clinical practice experimental study human monoclonal antibodies immunoregulation improved in utero innovative technologies insight model development mortality neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel pandemic disease pediatric human immunodeficiency virus perinatal HIV postnatal pre-clinical prevent response simian human immunodeficiency virus time use virology

项目摘要

The existing knowledge of perinatal HIV-1 infection on developing immunity is limited, and a need exists to define the unique characteristics of immunity in infants that influence pediatric disease progression. The long- term goal of this project is to develop a pathway to achieve durable remission for infants in the absence of prolonged drug treatment. The central hypothesis is that understanding the quality and magnitude of the innate and adaptive immune systems of newborns in response to HIV-1 infection is essential for developing better strategies to achieve durable remission of HIV-1. The project will first address pathogenesis of perinatal HIV infection, with and without ART, using a proven pre-clinical model of SHIV infection in newborn macaques. For human infants, the incidence of infection is greatest between late stages of gestation and early weeks of postpartum. Infection in utero or peripartum without early ART intervention leads to high mortality in the first year of life. The risk of death is about half as great if infection occurs postnatally during breastfeeding. To mirror peripartum infection, newborn macaques will be infected within the first few weeks of life (< 2 weeks old) with SHIV by the oral route. Using serial sacrifices, the macaque experiments will allow for a comprehensive evaluation of B cell and T cell function in blood, and multiple lymphoid and gut tissues at specific timepoints during infection. The effect of an immature immune system at the time of infection on immune dysfunction and disease progression will be assessed and compared between groups of animals that receive daily ART starting within days of infection versus no ART groups. In addition to studying the impact of viremia on immune cell function and viral reservoir kinetics, experiments in Years 2–4 will examine viremia rebound in infants after modulating and potentially protecting adaptive immunity by limiting viral replication during the first week of infection with ART. To mitigate immune dysregulation, further modulation of immune responses will be assessed with the addition of potent neutralizing antibodies to complement the intervention strategy during and just prior to ART cessation. Together, these studies will inform current clinical practices that are poised to advance very early ART in circumstances of in utero or intrapatrum infection, but are challenged by incomplete pre-clincal data to guide future practices at or near delivery. The proposed approaches and methodologies that can be used in a nonhuman primate model but are not feasible in human infants will provide mechanistic evidence of when and how active viral reservoirs can be prevented, reduced, or eliminated. Innovative technologies, including the use of a new Primate Multimodal Imaging Core at the Oregon National Primate Research Center, will provide access to state-of-the-art reagents and expertise for imaging viral latency, reactivation, and treatment in macaques in real time using PET scans. The questions addressed and answered in these studies will provide a strong foundation for future expansion of optimal approaches to decrease the morbidity and mortality associated with perinatal HIV-1 infection.

现有的有关围产期HIV-1感染对发展免疫力的知识是有限的，并且需要定义影响小儿疾病进展的婴儿免疫的独特特征。长期该项目的术语目标是开发一条途径，以在没有长时间的药物治疗。中心假设是了解先天的质量和大小以及针对HIV-1感染的新生儿的自适应免疫系统对于更好地发展实现HIV-1持久缓解的策略。该项目将首先解决围产期HIV的发病机理感染，有或没有艺术，使用新生儿猕猴中经过验证的SHIV感染的临床前模型。为了人类婴儿，妊娠后期和早期几周之间感染的事件是最大的产后。在没有早期艺术干预的情况下，子宫或外围感染导致高死亡率在第一次生命年。如果感染在母乳喂养期间出现，死亡的风险大约是一半。到镜子外围感染，新生儿猕猴将在生命的头几周内感染（<2周大）在口腔路线上进行Shiv。使用串行牺牲，猕猴实验将允许全面在特定时间点评估血液中B细胞和T细胞功能的评估在感染期间。感染时未成熟免疫系统对免疫功能障碍和将评估和比较接受每日艺术开始的动物组之间的疾病进展在感染与无艺术团体的几天之内。除了研究病毒血症对免疫细胞的影响功能和病毒储层动力学，2 - 4年的实验将检查婴儿后的病毒血症反弹通过限制病毒复制的第一周，调节和潜在地保护适应性免疫艺术感染。为了减轻免疫失调，免疫反应的进一步调节将是通过添加潜在中和抗体来评估，以完成和就在艺术停止之前。这些研究一起将为当前中毒的临床实践提供信息在子宫内或帕特鲁姆内感染的情况下，非常早期的艺术，但不完整挑战前数据前数据指导未来或接近交付的实践。提出的方法和方法可以在非人类私人模型中使用，但在人类婴儿中不可行会提供机械可以预防，减少或消除活动病毒储层的何时何时何地。创新的技术，包括在俄勒冈国家灵长类动物上使用新的灵长类动物多模式成像核心研究中心将提供最先进的试剂和用于成像病毒潜伏期的专业知识，重新激活，并使用PET扫描实时在猕猴中进行治疗。解决并回答的问题在这些研究中，将为未来扩展最佳方法的基础，以减少与围产期HIV-1感染相关的发病率和死亡率。