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: 9977916
• 负责人: Nancy L Haigwood
• 金额: $ 79.74万
• 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/9977916
• 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; 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; 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; mortality risk; neonatal infection; 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.

现有关于围产期感染艾滋病毒-1对免疫形成的了解有限，有必要 明确影响儿科疾病进展的婴儿免疫的独特特征。长的- 该项目的长期目标是开发一种途径，以实现婴儿在缺乏 延长药物治疗时间。中心假设是，理解先天的质量和大小 新生儿对HIV-1感染的适应性免疫系统对于更好地发育是必不可少的 实现艾滋病毒-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。 在新生儿猕猴中使用经过验证的新城疫病毒感染的临床前模型，在接受和不接受抗逆转录病毒治疗的情况下进行感染。为 人类婴儿，感染的发生率在妊娠晚期和妊娠早期几周最高。 产后。未早期抗逆转录病毒治疗的宫内或围产期感染可导致高死亡率 生命的一年。如果在母乳喂养期间发生出生后感染，死亡风险大约是前者的一半。至 镜像围产期感染，新生猕猴将在出生后的头几周内感染(&lt；2周大) 与希夫通过口述途径。使用一系列的牺牲，猕猴实验将允许全面的 特定时间点血液及多种淋巴组织和肠道组织中B细胞和T细胞功能的评价 在感染期间。感染时不成熟的免疫系统对免疫功能障碍和 疾病进展将在接受每日抗逆转录病毒治疗的动物组之间进行评估和比较 在感染后的几天内与没有艺术团体相比。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，2-4年的实验将检查婴儿在以下情况下的病毒血症反弹 通过限制病毒复制来调节和潜在地保护获得性免疫 对艺术的感染。为了缓解免疫失调，免疫反应的进一步调节将是 通过添加有效的中和抗体进行评估，以补充干预策略 就在艺术停止之前。总而言之，这些研究将为当前的临床实践提供信息，这些实践有望 在宫内或宫内感染的情况下非常早期地开展ART，但受到不完全的挑战 临床前数据，以指导未来的做法，在交付或接近交付。建议的方法和方法 可以用于非人类灵长类动物模型，但在人类婴儿身上不可行将提供机械性 关于何时以及如何预防、减少或消除活跃的病毒库的证据。创新型 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， 重新激活，并使用PET扫描对猕猴进行实时治疗。已解决和回答的问题 在这些研究中，将为今后扩大减少 围产期HIV-1感染的发病率和死亡率。