The Latent HIV Reservoir in Early-treated Thai Children

早期治疗的泰国儿童中的潜在艾滋病病毒库

• 批准号: 8727128
• 负责人: Jintanat Ananworanich
• 金额: $ 52万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727128
• 关键词: Acute; Adult; Age; Age-Months; Anti-Retroviral Agents; Antibodies; Asia; Asians; Biological Markers; Birth; CD4 Positive T Lymphocytes; Caring; Cells; Child; Child Mortality; Chronic; Collaborations; Commit; Country; DNA; Data; Diagnosis; Disease remission; Enrollment; Environment and Public Health; Epidemic; Exhibits; Goals; Guidelines; HIV; HIV Infections; Health; Health Policy; Human; Immune response; Immunologics; Income; Infant; Inflammation; Intervention; Knowledge; Lead; Life; Maintenance; Measures; Mississippi; Outcome; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Policy Maker; Predictive Factor; Pregnant Women; Prevention; Prophylactic treatment; Public Health; Quality of life; RNA; RNA replication; Reporting; Research; Research Personnel; Testing; Thailand; Time; Translating; United States National Institutes of Health; Vertical Disease Transmission; Viral; Viremia; Work; antiretroviral therapy; authority; cell mediated immune response; cohort; coping; design; experience; high risk; high risk infant; immune activation; improved; infancy; innovation; pediatric human immunodeficiency virus; prospective; public health relevance; public health research; response; standard of care; therapy design; transmission process; viral RNA

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.

描述（由申请人提供）：全球，艾滋病毒目前遭受3400万人的折磨，其中包括330万儿童。其中，分别有500万和15万，居住在人口最多的大陆（42亿人）中。随着抗逆转录病毒疗法（ART）的可用性，儿童死亡率正在降低，但艾滋病毒的儿童继续应对艾滋病毒作为一种慢性，高度污名化和可传染的疾病。艾滋病毒的持久性尽管成功，这是长期维持稳定储层在长寿细胞中的结果。 为了提高我们对儿童的艾滋病毒潜伏期的理解，必须量化储层大小及其在早​​期治疗的儿童中的复制能力，进而为治疗方法提供干预措施，我们将确定限制性HIV储备库大小的确定因素，并在婴儿期间接受Art治疗的儿童中诱导的HIV RNA RNA的重复。目的是确定儿童艺术发作和持续时间的关键时机，这将导致良好的储层轮廓，定义为在CD4+ T细胞中活化后，外周血单核细胞中具有低至不可检测的综合HIV DNA水平，以及无法检测到的诱导HIV HIV RNA水平。我们的中心假设是，早期的艺术启动（D8周）和较长的艺术持续时间（E1年）将与储层较低有关。我们将通过在生命的头六个月中招募260名启动艺术的儿童来检验中心假设。这将包括长期抑制病毒的大儿童和新感染的婴儿，他们在出生时启动三周抗逆转录病毒（ARV）预防（由于是由于是由于 艾滋病毒感染的高风险），然后在确认艾滋病毒时过渡到三重艺术。研究 将测量HIV储层大小和可复制性（综合HIV DNA和可诱导HIV RNA），储层大小的间接标记（HIV特异性免疫反应）的直接标记，以及储层大小的预测因素（病毒抑制，炎症，炎症和低度层次的病毒率）。我们将利用现有的预防母亲传播和小儿艾滋病毒公共卫生和研究网络的强度，以及2013年泰国公共卫生部（MOPH）指南（MOPH）指南建议，建议在所有HV诊断的高危婴儿和早期婴儿诊断后出生后三重ARV预防，所有HV诊断。该项目得到了泰国MOPH的大力支持，将对公共卫生产生巨大影响。此外，在泰国和其他亚洲国家循环的CRF01_AE HIV进化枝可能与对HIV持久性重要的独特免疫和病毒学反应有关，这项研究将是评估亚洲儿童艾滋病毒持久性的少数人之一。我们的长期目标是将对早期治疗儿童的潜在水库的知识转化为 会导致艾滋病毒治愈的干预措施。