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

• 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
• 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

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.

关于围产期HIV-1感染对免疫力发育的影响的现有知识是有限的，需要 定义影响儿科疾病进展的婴儿免疫的独特特征。很长的- 该项目的长期目标是开发一种途径，在缺乏 长期药物治疗。核心假设是，理解先天性的质量和数量 新生儿的适应性免疫系统对HIV-1感染的反应是至关重要的， 实现HIV-1持久缓解的战略。该项目将首先解决围产期艾滋病毒的发病机制 感染，有和没有ART，使用新生猕猴中SHIV感染的经证实的临床前模型。为 在人类婴儿中，感染的发病率在妊娠晚期和妊娠早期最高。 产后子宫内感染或围产期感染而不进行早期抗逆转录病毒治疗， 年寿命。如果感染发生在产后母乳喂养期间，死亡风险约为一半。到 镜像围产期感染，新生猕猴将在生命的前几周内感染（< 2周龄） 通过口服途径感染了SIV病毒利用连续的牺牲，猕猴实验将允许一个全面的 在特定时间点评价血液、多种淋巴和肠道组织中的B细胞和T细胞功能 在感染期间。感染时不成熟的免疫系统对免疫功能障碍的影响， 将评估疾病进展，并在开始每天接受ART的动物组之间进行比较。 在感染的几天内与没有ART组相比。除了研究病毒血症对免疫细胞的影响， 功能和病毒库动力学，第2-4年的实验将检查婴儿中的病毒血症反弹， 通过限制病毒复制来调节和潜在地保护适应性免疫， 为了减轻免疫失调，将进一步调节免疫应答。 通过添加强效中和抗体进行评估，以补充治疗期间的干预策略， 在ART停止之前。总之，这些研究将为当前的临床实践提供信息， 在子宫内或子宫内感染的情况下，推进非常早期的ART，但受到不完全的挑战。 临床前数据，以指导未来的做法或接近交付。拟议的方针和方法， 可用于非人灵长类动物模型，但在人类婴儿中不可行， 何时以及如何预防、减少或消除活跃病毒储库的证据。创新 技术，包括在俄勒冈州国家灵长类动物中心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成像病毒潜伏期的专业知识， 再激活，并使用PET扫描在猕猴中进行真实的实时治疗。提出和回答的问题 在这些研究中，将为未来扩大最佳方法以减少 与围产期HIV-1感染相关的发病率和死亡率。