Early neonatal treatment and immune quiescence

新生儿早期治疗和免疫静止

• 批准号: 8727251
• 负责人: Louise Kuhn
• 金额: $ 93.97万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727251
• 关键词: Adult; Age; Anatomy; Anti-Retroviral Agents; Antibody Formation; Automobile Driving; Birth; Blood; Blood specimen; CCR5 gene; Caring; Case Study; Cells; Child; Chronic; Clinical; Clinical Services; Clinical Trials; Color; Data; Development; Diagnostic tests; Early treatment; Eligibility Determination; Event; Feces; Flow Cytometry; Gastrointestinal tract structure; HIV; HIV Antibodies; HIV Seropositivity; Hospitals; Hour; Human; Human immunodeficiency virus test; Immune; Immune system; Immunity; Infant; Infection; Intervention; Intestines; Laboratories; Life; Maintenance; Measures; Memory; Methods; Mississippi; Monitor; Mothers; Neonatal; Newborn Infant; Outcome; Parents; Pediatric Hospitals; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Process; Public Health; Quality of life; Recruitment Activity; Regimen; Relative (related person); Reporting; Research Infrastructure; Rest; Role; Safety; Sampling; Schedule; Services; Site; South Africa; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Viral; antiretroviral therapy; arm; base; clinical care; cohort; design; functional outcomes; improved; infant outcome; inflammatory marker; innovation; meetings; peripheral blood; point of care; programs; public health relevance; success; transmission process

DESCRIPTION (provided by applicant): The long-lasting viral reservoir in resting CD4 memory cells and other anatomic sanctuaries requires that antiretroviral therapy (ART) be continued life-long. The recent report of the infant in Mississippi who started treatment within 30 hours of birth and who has been able to maintain viral suppression off treatment raises the tantalizing possibility that establishment of the viral reservoir may be avoidable in some infants. Limitations of this single case report necessitate urgent replication as the potential public healt benefits of the intervention are profound. We propose a single-arm clinical trial in Johannesburg, South Africa, to replicate the Mississippi case in a more robust number of infants. Our trial is designed to test whether initiation of ART within 48 hours of birth has the potential to allow the majority of HIV-infected infants to safely discontinue ART without viral rebound. The context of starting ART within hours of birth and stopping it 18 months later provides an unprecedented opportunity to elucidate mechanisms involved in the establishment and maintenance of viral reservoir. In the context of this unique trial, we will collect samples before, during and after AR cessation to investigate potential mechanisms driving the establishment of the viral reservoir. Following the exciting new findings from the Mississippi child, we hypothesize that infant immunological developmental maturity is one of the critical parameters influencing the success of early treatment. ART given at birth is not only close in time to acquisition of infection but is given during a developmentally-critical time period when the immune system is transitioning to its mature form and is at its most quiescent. We will also recruit a carefully-selected observational cohort of infants 4-12 weeks of age initiating and continuing ART in the standard way from routine clinical services. We will investigate whether lesser CCR5 and CD2 expression on T-cells, a smaller pool of CD4 memory cells, reduced markers of T-cell activation, and larger proportions of regulatory (suppressive) T-cells (T-regs) relative to Th17 cells will be associated with more limited seeding and greater decay of the viral reservoir when ART is started at a young age. We will also investigate whether markers in infant stool samples can be used as a non-invasive method of defining relevant immune and HIV-specific parameters associated with smaller viral reservoirs.

描述（由申请人提供）：静止的CD4记忆细胞和其他解剖学庇护所中的持久病毒储层要求抗逆转录病毒疗法（ART）继续终身。密西西比州婴儿的最新报告在30岁以内开始治疗 出生时间以及能够维持病毒抑制的治疗的人提出了诱人的可能性，即在某些婴儿中可以避免建立病毒储量。 该单个案例报告的局限性需要紧急复制，因为干预的潜在公共愈合益处是深远的。我们建议在南非约翰内斯堡进行单臂临床试验，以更大的婴儿数量复制密西西比州病例。我们的试验旨在测试出生后48小时内的艺术是否有可能使大多数受HIV感染的婴儿在没有病毒反弹的情况下安全停止艺术。 18个月后，在出生几小时内开始艺术的背景为阐明参与病毒储层的建立和维持涉及的机制提供了前所未有的机会。在这项独特的试验的背景下，我们将在AR停止之前，之中和之后收集样品，以研究推动病毒储层建立的潜在机制。在密西西比儿童的激动人心的新发现之后，我们假设婴儿免疫发育成熟度是影响早期治疗成功的关键参数之一。出生时提供的艺术不仅是收到感染的时间，而且是 在免疫系统过渡到其成熟形式并且最静止的发展时期，给出了至关重要的时期。我们还将从常规临床服务中以标准的方式招募4-12周启动和持续艺术的婴儿的仔细观察队列。我们将研究在T细胞上的CCR5和CD2表达较小，CD4存储细胞的较小库，T细胞激活的标记减少以及相对于TH17细胞的调节（抑制）T细胞（T-REGS）的比例较大，将与年龄在Art Art Art Art Art Art Art Art Art Art Art时相对于更有限的播种和更大的衰减。我们还将研究婴儿粪便样品中的标记是否可以用作定义与较小病毒储层相关的相关免疫和HIV特异性参数的非侵入性方法。