Maximising Cure Potential in Paediatric HIV Infection

最大限度地提高儿童艾滋病毒感染的治愈潜力

• 批准号: 9750633
• 负责人: PHILIP J GOULDER
• 金额: $ 29.63万
• 依托单位: UNIVERSITY OF OXFORD
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750633
• 关键词: Address; Adult; Aftercare; Age; Applications Grants; Autologous; Bedside Testings; Birth; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Clinic; Cohort Studies; Collaborations; Cytotoxic T-Lymphocytes; Disease remission; Environment; Funding; Goals; HIV; HIV Infections; HLA-B Antigens; Health; Hour; Immune; Immune system; Immunologics; Individual; Infant; Infection; Infrastructure; Interruption; Life; Literature; Mediating; Minority; Mothers; Play; Role; Shock; South Africa; T-Lymphocyte Subsets; Testing; Trust; Variant; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Replication; aged; antiretroviral therapy; arm; cohort; design; in utero; in utero diagnosis; infancy; insight; neonatal period; outcome prediction; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; predictive marker; response; standard of care; transcriptomics; virology

ABSTRACT The overarching aim of this grant proposal is to define and understand the conditions that create the best chance for cure or remission in HIV infection. There is a strong rationale for believing that in utero (IU) infection may provide the most promising starting point, because of the potential to initiate antiretroviral therapy (ART) within hours of birth, and because the immunotolerant environment in early life may reduce the ability of HIV to establish large viral reservoirs early in the course of infection. Aim 1 focuses on mechanisms of minimising the size of the viral reservoir in paediatric infection. Aim 2 addresses the ability of the effector arm of the paediatric immune system to eradicate HIV-infected cells as part of shock-and-kill strategies. Finally, to tackle the issue of how to identify children who will and who will not be suitable for ART treatment interruption, Aim 3 seeks to identify predictors of outcome post-treatment interruption. To approach these aims, we will study the cohorts of HIV-infected children we have generated over the past two decades of collaborations in South Africa. This includes two cohorts of HIV-infected children in whom ART was initiated in the neonatal period, one a historical cohort from 2002-2005, the other a current cohort in whom ART is initiated within 48hrs of birth. In addition we have identified in South Africa ~300 ART-naïve children aged >5yrs who have maintained normal health and normal-for-age CD4 counts (>750 cells/mm3), whom we have termed `paediatric non-progressors' or `PNP'. These PNP represent approximately 5-10% of HIV-infected children. Some of these ART-naïve children we have followed throughout childhood (ie from 0- 10yrs of age) and beyond, and these children still attend our clinics with their mothers today. These cohorts of children and mother-child pairs together provide us with unique opportunities to address our study aims that are fundamental to understanding how to achieve the best chance of HIV cure or remission. In Aim 1, Mechanisms of minimising the size of the viral reservoir in paediatric infection, we will determine the impact on the size of viral reservoir of ART initiation at 1-2 weeks of age – the current standard of care in South Africa – versus initiation within the first 1-2 days of life. In this sub-aim, we will build upon the infrastructure already established through our Wellcome Trust funded study started in 2015 in South Africa designed to establish the feasibility of point-of-care testing to diagnose in utero infection and initiated ART within the first 48hrs of life. We will also examine the infuence of viral factors such as viral replicative capacity - shown to be important in adults - on reservoir size, taking advantage of the opportunity to study transmitted virus within hours of birth. Finally we will test the hypothesis that paediatric non- progressors (defined above), in whom we have shown low levels of HIV infection in the long-lived Tscm and Tcm CD4 T-cell subsets compared to the Tem compartment, will show rapid and substantial decline in size of viral reservoirs on ART, as a result of the cellular localisation of HIV infection. In Aim 2, Mechanisms of optimal effector function for reservoir eradication, we argue that HIV-specific cytotoxic T lymphocytes (CTL) are likely to play an important role in eliminating HIV-infected cells that comprise the viral reservoir; however, control of viraemia is highly unusual in ART-naïve paediatric infection. Among ~300 ART-naïve paediatric non-progressors, we have identified <10% who have either reached undetectable viral loads (<20 copies/ml), or stable viral loads of <1000 c/ml. In contrast to adult elite controllers, control of viraemia in paediatric infection arises only after several years of infection, it is usually transient, and it appears unrelated to expression of protective HLA molecule such as HLA- B*57/58:01/81:01. Finally, unlike adults, HIV-infected children typically can generate CTL responses against CTL escape variants: potentilly this is the ultimate solution to HIV Study of these viraemic controllers longitudinally, in some cases from infancy, and comparison with viraemic non-controller children, will provide critical insights into the mechanisms of viraemic control in HIV-infected children. In Aim 3, Biomarkers predicting outcome post-treatment interruption, we propose the hypothesis that factors contributing to low viral reservoirs in the key, long-lived T cell subsets (Tscm and Tcm) also mediate HIV non-progression. In this aim we will first seek to identify features distinguishing progression from non- progression in longitudinally tracked children. In the second sub-aim, we will test the ability of these markers to predict outcome in a historical treatment interruption cohort of infants in whom ART was initiated at 4 weeks' age and interrupted after 12 months. Post-treatment interruption, 40% of infants progressed rapidly to restart ART within a median of 0.23yrs; in contrast, another 40% initiated ART >5yrs later.

摘要 这项赠款提案的首要目标是定义和理解创造最佳 艾滋病毒感染治愈或缓解的机会。有一个强有力的理由相信在子宫内(IU) 感染可能是最有希望的起点，因为它有可能启动抗逆转录病毒。 在出生后几个小时内进行治疗(ART)，因为早期生命中的免疫耐受环境可能会减少 艾滋病毒在感染早期建立大型病毒库的能力。目标1侧重于 减少儿科感染病毒库大小的机制。目标2解决的是 儿科免疫系统的效应器手臂，作为休克和杀死的一部分，用于根除艾滋病毒感染的细胞 战略。最后，解决如何确定谁将适合谁不适合的问题 ART治疗中断，AIM 3试图确定治疗后中断结果的预测因素。 为了实现这些目标，我们将研究我们过去产生的感染艾滋病毒的儿童队列。 二十年来在南非的合作。这包括两组感染艾滋病毒的儿童，其中 抗逆转录病毒治疗是在新生儿期开始的，一个是2002-2005年的历史队列，另一个是当前的队列 其中的艺术在出生后48小时内开始。此外，我们已经在南非发现了大约300名天真的艺术 5岁的儿童，保持正常健康和正常年龄的CD4计数(750个/mm~3)， 我们称之为‘儿科无进展者’或‘PNP’。这些PNP约占5%-10% 感染艾滋病毒的儿童。其中一些我们从小到大都在跟踪的艺术天真的孩子(即从0到 10岁以上的儿童，这些儿童今天仍然和他们的母亲一起来我们的诊所。这些队列 儿童和母子配对一起为我们提供了独特的机会来实现我们的研究目标 这对于了解如何获得最好的艾滋病毒治愈或缓解机会至关重要。 在目标1，最小化儿科感染中病毒库大小的机制，我们将 确定在1-2周龄时启动ART对病毒库大小的影响-当前 南非的护理标准--而不是在生命的头1-2天内开始。在这个子目标中，我们将 建立在我们通过惠康信托资助的研究已经建立的基础设施上，这项研究于2015年开始 南非旨在建立诊断宫内感染的护理点检测的可行性 在生命的最初48小时内发起了艺术。我们还将检查病毒因素的影响，如病毒 复制能力-被证明在成年人中很重要-关于水库大小，利用机会 研究出生后数小时内传播的病毒。最后，我们将检验这一假设，即儿科非 进展者(上面定义)，我们在长期存活的TSCM和TSCM中显示出低水平的艾滋病毒感染 Tcm的CD4T细胞亚群与Tem相比，在大小上将显示出快速而实质性的下降 由于艾滋病毒感染的细胞局部化，ART上的病毒库。 在目标2中，最佳效应功能的机制，我们认为，艾滋病毒特异性 细胞毒性T淋巴细胞(CTL)在清除HIV感染细胞方面可能发挥重要作用 包括病毒库；然而，在幼稚的儿科感染中，病毒血症的控制非常不寻常。 在大约300名天真的儿科无进步患者中，我们发现有10%的人要么达到了 无法检测到的病毒载量(&lt；20拷贝/毫升)，或稳定的病毒载量&lt；1000 c/ml。与成人精英形成对比 控制员说，控制儿科感染中的病毒血症是在感染几年后才出现的，通常是 暂时性的，似乎与保护性的人类白细胞抗原分子的表达无关。 B*57/58：01/81：01。最后，与成年人不同的是，感染艾滋病毒的儿童通常可以产生针对 CTL逃逸变异体：这可能是对这些病毒携带者进行HIV研究的最终解决方案 从纵向来看，在某些情况下，从婴儿期开始，并与病毒流行型非控制性儿童进行比较，将提供 对艾滋病毒感染儿童的病毒病控制机制的重要见解。 在目标3，生物标记物预测治疗后中断的结果，我们提出了假设 在关键的、长寿的T细胞亚群(TSCM和Tcm)中，导致低病毒储存库的因素也起到了中介作用 艾滋病毒无进展。在这个目标中，我们将首先寻求识别区分进展和非进展的特征 纵向追踪儿童的进展情况。在第二个分目标中，我们将测试这些标记的能力 预测在4岁开始抗逆转录病毒治疗的婴儿的历史治疗中断队列的结果 几周大，12个月后中断。治疗中断后，40%的婴儿进展迅速 在中位数0.23年内重新开始抗逆转录病毒治疗；相比之下，另有40%的人在5年后开始抗逆转录病毒治疗。