Maximising Cure Potential in Paediatric HIV Infection

摘要 这项拨款提案的首要目标是定义和理解创造最佳环境的条件。 治愈或缓解艾滋病毒感染的机会。有一个强有力的理由相信，在子宫（IU） 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 在出生后数小时内接受抗逆转录病毒治疗（ART），并且由于早期生命中的免疫耐受环境可能会减少 艾滋病毒在感染过程早期建立大型病毒库的能力。目标1侧重于 最小化儿科感染中病毒储库大小的机制。目标2： 儿科免疫系统的效应臂，作为休克和杀死的一部分， 战略布局最后，为了解决如何确定哪些儿童适合和哪些儿童不适合 ART治疗中断，目标3旨在确定治疗中断后结局的预测因素。 为了实现这些目标，我们将研究我们过去产生的艾滋病毒感染儿童的队列 在南非合作了二十年。这包括两组艾滋病毒感染儿童，其中 抗逆转录病毒治疗开始于新生儿期，一个是2002-2005年的历史队列，另一个是当前队列 在出生后48小时内开始抗逆转录病毒治疗的患者。此外，我们还在南非确定了约300例ART初治患者 年龄> 5岁的儿童，保持正常健康和年龄正常的CD 4计数（>750个细胞/mm 3）， 我们称之为“儿科无进展者”或“PNP”。这些PNP约占 感染艾滋病毒的儿童。这些艺术天真的孩子，我们已经遵循整个童年（即从0- 10岁）及以上，这些孩子今天仍然和他们的母亲一起参加我们的诊所。这些队列 孩子和母亲-孩子对一起为我们提供了独特的机会，以解决我们的研究目标 这对于理解如何获得艾滋病治愈或缓解的最佳机会至关重要。 在目标1，最大限度地减少儿科感染中病毒储库大小的机制中，我们将 确定在1-2周龄时开始ART对病毒储存库大小的影响-目前 南非的标准治疗-与出生后1-2天内开始治疗相比。在这个子目标中，我们将 在2015年开始的惠康信托基金资助的研究中已经建立的基础设施上， 南非旨在建立即时检测的可行性，以诊断子宫内感染， 在生命的前48小时内开始ART。我们还将研究病毒因素的影响，如病毒 复制能力-在成人中很重要-对水库大小，利用机会 研究出生后数小时内的传播病毒。最后，我们将测试的假设，儿科非- 进展者（如上定义），其中我们在长寿Tscm中显示出低水平的HIV感染， 与Tem区室相比，Tcm CD 4 T细胞亚群的大小将显示快速和大幅下降 由于HIV感染的细胞定位，ART上的病毒储库。 在目标2中，消除储库的最佳效应功能的机制，我们认为， 细胞毒性T淋巴细胞（CTL）可能在清除HIV感染细胞中起重要作用， 包括病毒储库;然而，在ART初治儿科感染中，病毒血症的控制非常罕见。 在约300例ART初治的儿科非进展者中，我们发现<10%的患者达到了 检测不到的病毒载量（<20拷贝/ml），或<1000 μ C/ml的稳定病毒载量。与成人精英相比， 控制者，儿科感染中病毒血症的控制只有在感染数年后才出现，通常是 短暂的，并且似乎与保护性HLA分子如HLA-1的表达无关。 B*57/58：01/81：01。最后，与成人不同，感染HIV的儿童通常可以产生CTL反应， CTL逃逸变异体：这可能是HIV的最终解决方案这些病毒血症控制者的研究 纵向，在某些情况下，从婴儿期，并与病毒血症非控制儿童比较，将提供 对HIV感染儿童病毒血症控制机制的重要见解。 在目标3中，预测治疗中断后结果的生物标志物，我们提出假设， 在关键的、长寿的T细胞亚群（Tscm和Tcm）中，有助于降低病毒储库的因素也介导 HIV无进展。在这个目标中，我们将首先寻求识别区分进展与非进展的特征。 纵向跟踪儿童的进展。在第二个子目标中，我们将测试这些标记的能力 预测在4岁时开始ART的婴儿历史治疗中断队列的结局 周龄，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ART;相反，另有40%的患者在> 5年后开始ART。

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.