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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的该拨款提案的总体目标是定义和了解创造最佳条件的条件有充分理由相信子宫内 (IU) 感染有治愈或缓解的机会。感染可能提供最有希望的起点，因为有可能启动抗逆转录病毒治疗出生后数小时内进行治疗（ART），并且因为生命早期的免疫耐受环境可能会降低目标 1 重点关注 HIV 在感染过程早期建立大型病毒库的能力。目标 2 旨在最大限度地减少儿科感染病毒库的大小。儿科免疫系统的效应臂，作为休克和杀伤的一部分来根除感染艾滋病毒的细胞最后，解决如何识别哪些孩子适合和哪些孩子不适合的问题。 ART 治疗中断，目标 3 旨在确定治疗中断后结果的预测因素。为了实现这些目标，我们将研究过去产生的艾滋病毒感染儿童群体在南非进行了二十年的合作，其中包括两组感染艾滋病毒的儿童。 ART在新生儿期开始，一个是2002-2005年的历史队列，另一个是当前队列此外，我们在南非发现了大约 300 名未接受过 ART 治疗的人。年龄 >5 岁且保持正常健康和正常年龄 CD4 计数（>750 个细胞/mm3）的儿童，我们将其称为“儿科非进展者”或“PNP”，这些 PNP 约占其中的 5-10%。我们在整个童年时期（即从 0- 10 岁）及以上，这些孩子至今仍与他们的母亲一起到我们的诊所就诊。儿童和母子对在一起为我们提供了实现学习目标的独特机会这对于了解如何实现艾滋病毒治愈或缓解的最佳机会至关重要。在目标 1，最小化儿科感染病毒库大小的机制中，我们将确定 1-2 周龄时开始 ART 对病毒库大小的影响 – 目前南非的护理标准——与出生后 1-2 天内开始的护理相比，我们将在这个分目标中。建立在我们 2015 年开始的 Wellcome Trust 资助的研究中已经建立的基础设施的基础上南非旨在建立即时检测诊断子宫内感染和感染的可行性在出生后 48 小时内开始 ART 我们还将检查病毒等病毒因素的影响。复制能力 - 被证明对成年人很重要 - 取决于储存库的大小，利用机会研究出生后数小时内传播的病毒，最后我们将检验儿科非传染性病毒的假设。进展者（如上定义），我们在他们的长寿 Tscm 中显示出低水平的 HIV 感染， Tcm CD4 T 细胞亚群与 Tem 隔室相比，将显示出尺寸快速且大幅下降由于 HIV 感染的细胞定位，ART 上病毒库的减少。在目标 2：消灭病毒库的最佳效应器功能机制中，我们认为 HIV 特异性细胞毒性 T 淋巴细胞 (CTL) 可能在消除 HIV 感染细胞方面发挥重要作用，这些细胞包括病毒库；然而，在未接受过 ART 的儿科感染中，控制病毒血症是非常不寻常的。在约 300 名未接受过 ART 治疗的儿科非进展患者中，我们发现 <10% 的患者已达到与成人精英相比，无法检测到的病毒载量（<20 拷贝/毫升）或稳定的病毒载量<1000 c/毫升。控制者，儿科感染病毒血症的控制只有在感染几年后才会出现，通常是短暂的，并且它似乎与保护性 HLA 分子的表达无关，例如 HLA- B*57/58:01/81:01 最后，与成人不同，感染艾滋病毒的儿童通常可以产生针对其的 CTL 反应。 CTL 逃逸变体：这可能是这些病毒血症控制者的 HIV 研究的最终解决方案纵向来看，在某些情况下从婴儿期开始，并与病毒血症非控制儿童进行比较，将提供对艾滋病毒感染儿童病毒血症控制机制的重要见解。在目标 3，预测治疗中断后结果的生物标志物中，我们提出以下假设：导致关键的长寿命 T 细胞亚群（Tscm 和 Tcm）中病毒储量较低的因素也会介导在此目标中，我们将首先寻求识别区分进展与非进展的特征。在纵向跟踪的儿童中的进展在第二个子目标中，我们将测试这些标记的能力。预测历史治疗中断队列中 4 岁开始 ART 的婴儿的结果周龄和 12 个月后中断治疗，40% 的婴儿病情进展迅速。中位数为 0.23 年内重新开始 ART；相比之下，另有 40% 的患者在 5 年以上后开始接受 ART。