The Latent HIV Reservoir in Early-treated Thai Children

描述(申请人提供)：在世界范围内，艾滋病毒目前困扰着3400万人，其中包括330万儿童。在这些人中，亚洲是人口最多的大陆(42亿人)，其中分别有500万人和15万人感染艾滋病毒。随着抗逆转录病毒疗法(ART)的出现，儿童死亡率正在下降，但艾滋病毒携带者儿童继续将艾滋病毒作为一种慢性、高度耻辱和可传播的疾病来应对。尽管抗逆转录病毒疗法成功，但艾滋病毒的持续存在是长期维持长期存活细胞中稳定的储存库的结果。 量化接受早期治疗的儿童的艾滋病毒储存库大小及其复制能力对于提高我们对儿童艾滋病毒潜伏期的了解是必要的，反过来，根据这一原理，我们将确定在婴儿期接受抗逆转录病毒治疗的儿童中限制艾滋病毒储存库大小和可诱导艾滋病毒RNA复制的决定因素。目的是确定儿童抗逆转录病毒治疗的关键发病时间和持续时间，这将导致良好的储存情况，即在外周血单核细胞中具有低水平或无法检测到的整合HIV DNA，以及在CD4+T细胞中激活时无法检测到可诱导的HIV RNA水平。我们的中心假设是，早期的ART启动(d8周)和较长的ART持续时间(e1年)将与较小的水库大小相关。我们将通过招募260名在出生后6个月内开始接受抗逆转录病毒治疗的儿童来检验这一中心假设。这将包括长期接受病毒抑制的较大儿童，以及新感染的婴儿，他们要么在4周后开始抗逆转录病毒治疗，要么在出生时就开始三重抗逆转录病毒(ARV)预防(由于 艾滋病毒感染的高风险)，然后在艾滋病毒确诊时过渡到三重抗逆转录病毒疗法。这项研究 在抗逆转录病毒治疗后，将测量HIV储存库大小和可复制性的直接标志物(整合的HIV DNA和可诱导的HIV RNA)，储存库大小的间接标志物(HIV特异性免疫反应)，以及储存库大小的预测因素(病毒抑制时间、炎症和低水平病毒血症)。我们将利用现有的预防母婴传播和儿科艾滋病毒公共卫生和研究网络的力量，以及2013年泰国公共卫生部(MOPH)指南的实施，该指南建议对高危婴儿在出生后进行三重ARV预防，并对所有感染HV的婴儿从1个月大开始进行早期诊断。该项目得到了泰国卫生部的大力支持，将对公众健康产生很大影响。此外，在泰国和其他亚洲国家流行的CRF01_AE艾滋病毒分支可能与独特的免疫学和病毒学反应有关，这对艾滋病毒的持久性很重要，这项研究将是少数几个评估亚洲儿童艾滋病毒持久性的研究之一。我们的长期目标是将接受早期治疗的儿童的潜在水库的知识转化为 将导致艾滋病毒治愈的干预措施。

DESCRIPTION (provided by applicant): Worldwide, HIV currently afflicts 34 million people including 3.3 million children. Of these, 5 million and 150,000, respectively, are living with HIV n Asia, the most populated continent (4.2 billion people). With the availability of antiretroviral therapy (ART), child mortality rates are decreasing, but children with HIV continue to cope with HIV as a chronic, highly stigmatized, and transmittable illness. Persistence of HIV despite successful ART is the result of the long-term maintenance of stable reservoirs in long-lived cells. Quantifying the reservoir size and its replicative capacity in early-treated children is necessary to elevate our understanding of HIV latency in children, and in turn, inform interventions for cure With this rationale, we will identify determinants for restricted HIV reservoir size and inducible HIV RNA replication in children treated with ART during infancy. The objective is to identify critical timing of ART onset and duration in children that will result in a favorable reservoir profile, defined as having low to undetectable levels of integrated HIV DNA in peripheral blood mononuclear cells and undetectable levels of inducible HIV RNA upon activation in CD4+ T cells. Our central hypothesis is that early ART initiation (d8 weeks) and long durations of ART (e1 year) will be associated with low reservoir size. We will test the central hypothesis by enrolling 260 children who have initiated ART during the first 6 months of life. This will include older children with long-term viral suppression, and newly infected infants who either commence ART after 4 weeks of age or initiate triple antiretroviral (ARV) prophylaxis at birth (due to being at high risk for HIV infection), and then transition to triple ART when HIV is confirmed. The study will measure direct markers of HIV reservoir size and replicability (integrated HIV DNA and inducible HIV RNA), indirect markers of reservoir size (HIV-specific immune responses), and predictive factors of reservoir size (timing of viral suppression, inflammation and low-level viremia) after ART. We will leverage the strength of existing prevention of mother-to-child transmission and pediatric HIV public health and research networks, and the implementation of the 2013 Thai Ministry of Public Health (MOPH) guideline recommending triple-ARV prophylaxis after birth for high-risk infants and earlier infant diagnosis starting at 1 month of age for all HV-exposed infants. This project has strong support from the Thai MOPH and will have high public health impact. Additionally, the CRF01_AE HIV clade that circulates in Thailand and other Asian countries may be associated with unique immunologic and virologic responses important for HIV persistence, and this study will be among the few to evaluate HIV persistence in Asian children. Our long-term goal is to translate knowledge on the latent reservoir in early-treated children into interventions that will lead to HIV cure.