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: 10203803
• 负责人: Nancy L Haigwood
• 金额: $ 74.06万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203803
• 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; infant infection; innovative technologies; insight; model development; mortality; mortality risk; 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 感染对免疫发展的现有了解有限，因此有必要 定义影响儿科疾病进展的婴儿免疫的独特特征。长- 该项目的长期目标是开发一条途径，在缺乏治疗的情况下实现婴儿的持久缓解。 长期药物治疗。中心假设是理解先天的质量和大小 新生儿应对 HIV-1 感染的适应性免疫系统对于更好地发育至关重要 实现 HIV-1 持久缓解的策略。该项目将首先解决围产期艾滋病毒的发病机制 使用经过验证的新生猕猴 SHIV 感染临床前模型，在有或没有 ART 的情况下进行感染。为了 人类婴儿在妊娠晚期和出生前几周感染的发生率最高 产后。如果没有早期 ART 干预，子宫内或围产期感染会导致第一时间的高死亡率 生命的一年。如果产后母乳喂养期间发生感染，死亡风险约为一半。到 镜像围产期感染，新生猕猴会在生命的最初几周内（<2周龄）被感染 通过口服途径感染 SHIV。通过连续牺牲，猕猴实验将能够进行全面的研究 评估特定时间点血液、多种淋巴组织和肠道组织中的 B 细胞和 T 细胞功能 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 将评估并比较每天接受 ART 的动物组之间的疾病进展 感染后几天内与无 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病毒血症反弹 通过在第一周限制病毒复制来调节和潜在地保护适应性免疫 ART 感染。为了减轻免疫失调，进一步调节免疫反应将是 通过添加有效的中和抗体进行评估，以补充期间和期间的干预策略 就在 ART 停止之前。总之，这些研究将为当前的临床实践提供信息，这些实践有望 在子宫内或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 临床前数据可指导未来在分娩时或临近分娩时的实践。所提出的方法和方法 可用于非人类灵长类动物模型，但在人类婴儿中不可行，将提供机械 何时以及如何预防、减少或消除活跃病毒库的证据。创新的 技术，包括在俄勒冈国家灵长类动物研究所使用新的灵长类动物多模态成像核心 研究中心将提供最先进的试剂和专业知识来成像病毒潜伏期， 使用 PET 扫描对猕猴进行实时重新激活和治疗。提出和回答的问题 这些研究将为未来扩展最佳方法以减少 与围产期 HIV-1 感染相关的发病率和死亡率。