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.

抽象的该赠款提案的总体目的是定义和了解创造最佳的条件治愈或缓解HIV感染的机会。相信在子宫（iu）有一个很强的理由感染可能是最有希望的起点，因为有可能启动抗逆转录病毒治疗（ART）在出生后数小时内，并且由于早期的免疫耐耐剂可能会减少在感染过程中，艾滋病毒在早期建立大型病毒库的能力。 AIM 1专注于在小儿感染中最小化病毒储层的大小的机制。 AIM 2解决了小儿免疫系统的效应臂，作为冲击和杀伤的一部分，对放射性HIV感染的细胞策略。最后，解决如何识别将会和不适合的孩子的问题 ART治疗中断，AIM 3试图识别治疗后中断结果的预测指标。为了实现这些目标，我们将研究我们过去产生的HIV感染儿童的同类南非的二十年合作。这包括两个艾滋病毒感染的儿童艺术是在新生儿时期开始的，一个是2002- 2005年的历史人群，另一个是当前队列在出生的48小时内开始艺术。此外，我们在南非确定了300次未经的艺术年龄> 5年的儿童保持正常健康和正常的CD4计数（> 750个细胞/mm3），我们称之为“儿科非培训者”或“ PNP”。这些PNP约占约5-10％艾滋病毒感染的孩子。我们在整个童年时期都遵循的一些未经艺术的孩子（即0- 10岁及以后的年龄，这些孩子今天仍然与母亲一起参加我们的诊所。这些队列儿童和母子搭配在一起为我们提供了独特的机会来解决我们的研究目标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AIM 1中，在小儿感染中最大程度地减少病毒储存库的大小的机制，我们将确定对1-2周龄的ART倡议病毒参与者规模的影响 - 当前南非的护理标准 - 在生命的前1-2天内与倡议相比。在这个子aim中，我们将建立在我们的惠康信托基金资助研究已经建立的基础设施的基础上，始于2015年南非旨在建立护理测试的可行性，以诊断子宫内感染和在生命的前48小时内开始艺术。我们还将检查病毒因素（例如病毒）的影响复制能力 - 在成人中很重要 - 在储层大小上，利用机会在出生后数小时内研究传播病毒。最后，我们将测试小儿非 - 进展者（上面定义），其中我们在长期寿命的TSCM中显示出低水平的HIV感染和与TEM隔室相比，TCM CD4 T细胞子集将显示大小的快速下降由于艾滋病毒感染的细胞定位，病毒储量在艺术方面。在AIM 2中，我们认为HIV特异性的最佳效应函数机制细胞毒性T淋巴细胞（CTL）可能在消除HIV感染的细胞中起重要作用构成病毒储层；然而，对病毒血症的控制在没有艺术的儿科感染中是高度不寻常的。在约有300个未经艺术的儿科非培训者中，我们已经确定了<10％的人无法检测到的病毒载荷（<20份/ml）或稳定的病毒载荷<1000 c/ml。与成人精英相反控制器，仅在感染了几年后才会出现对小儿感染中病毒血症的控制，通常是瞬态，它似乎与受保护的HLA分子（例如HLA-）的表达无关 B*57/58：01/81：01。最后，与成年人不同，感染HIV的儿童通常可以对 CTL逃生变体：可能是对这些病毒性控制器HIV研究的最终解决方案纵向，在某些情况下，从婴儿期开始以及与病毒性非控制者儿童进行比较，将提供对感染HIV感染儿童的病毒性控制机制的批判性见解。在AIM 3中，生物标志物预测结果后的结果中断，我们提出了这样的假设：在密钥，长寿命T细胞子集（TSCM和TCM）中导致低病毒库的因素也介导艾滋病毒非促进。在此目标中，我们将首先寻求确定区分进展与非非 - 的特征纵向追踪儿童的进展。在第二个子-IAM中，我们将测试这些标记的能力为了预测历史疗法中断的婴儿队列中的结果数周的年龄并在12个月后中断。治疗后中断，基础设施的40％迅速发展重新启动0.23岁的中位数；相比之下，另外40％的人在5年后开始了ART> 5年。