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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：
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
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/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

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.

现有的关于围产期HIV-1感染对免疫发育的认识有限，需要进一步研究