Molecular signatures of broad neutralization in HIV infected children

HIV感染儿童广泛中和的分子特征

• 批准号: 10159960
• 负责人: Wilton B Williams
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-06 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159960
• 关键词: 1 year old; 3 year old; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Antibody Response; Archives; B-Lymphocytes; Biological Specimen Banks; CD4 Positive T Lymphocytes; Cell physiology; Cells; Child; Childhood; Chronic; Cohort Studies; Development; Early identification; Enrollment; Environment; Epidemic; Epitopes; Frequencies; Functional disorder; Gene Expression Profile; Genes; Goals; Growth; HIV; HIV Infections; HIV vaccine; HIV-1; Immune; Immune response; Immunity; Immunization; Individual; Infant; International; Kinetics; Life; Longitudinal cohort; Maps; Measures; Mediating; Modeling; Molecular; Molecular Profiling; Mothers; National Institute of Child Health and Human Development; Natural Killer Cells; Pathway interactions; Peripheral Blood Mononuclear Cell; Plasma; Population; Prevention strategy; Proteins; Sampling; Site; Specificity; Target Populations; Testing; Time; Transcript; Vaccination; Vaccines; Virus; Youth; aged; base; cohort; design; experimental study; insight; neutralizing antibody; novel; pediatric human immunodeficiency virus; preventive intervention; response; sexual debut; transcriptome; transcriptome sequencing; vaccine candidate; vaccine development; vaccine evaluation; young adult

Abstract The burden of HIV among adolescents and young adults remains high with more than 30% of new HIV infections globally occurring among youth ages 15 to 24 years, making this a critical target population for prevention strategies. While induction of broadly neutralizing antibodies (bnAbs), is a major goal for an HIV vaccine, none of the candidate vaccines tested to date has been able to generate this sort of response. Remarkably, recent studies have indicated that HIV infected children develop broad neutralization earlier and more frequently than adults. To confirm these findings, we recently compared neutralizing antibody responses in a large cross-sectional cohort of HIV infected children aged 1-3 years old to that of chronically infected adults. By one year of age, the neutralization breadth in children was comparable to that of adults, confirming that HIV infected children are able to develop broad neutralization early. Interestingly, contrary to adults in which neutralization breadth is usually mediated by bnAbs of one or two specificities, in the majority of children, neutralization appeared to be mediated by a polyclonal response. This suggests that different mechanisms could drive the development of neutralization breadth in children and adults. Importantly, a recent transcriptome analysis revealed an association between the expression of a protein that regulates natural killer (NK) cell function (RAB11FIP5) and bnAb development in HIV-infected adults. Early life NK cells are functionally different from adults NK cells; and it is well established that the early life immune milieu is distinct from that of adults. Yet, whether the distinct early life immune environment or the expression of specific factors such as RAB11FIP5 are associated with early broad neutralization development in young children remains unknown. In this study, we therefore propose to test the hypothesis that a distinct host transcriptional profile is associated with the development of HIV-specific antibody neutralization breadth in early life, using archived, longitudinal samples from HIV-infected children enrolled in the Mother and Infant cohort study (MICS) and the NICHD International Site Development Initiative Pediatric study (NISDI). Our specific aims are: 1) To define the kinetics of development of broad neutralization in a longitudinal cohort of HIV-infected children; and 2) To evaluate the association between transcriptional profile and development of neutralization breadth in HIV-infected children. This study will enhance our current understanding on the kinetics of neutralization breadth development in HIV-infected children and provide novel insights on the molecular pathways leading to neutralization breadth development early in life. Altogether, this new information will guide the development of HIV vaccine strategies designed to protect prior to sexual debut. In addition, transcriptional signatures of broad neutralization could serve as markers for the early identification of immunization strategies with the potential to induce broad neutralization.

摘要 青少年和年轻人的艾滋病毒负担仍然很高，超过30%的新艾滋病毒感染者 全球15至24岁的青年中发生的感染，使其成为预防艾滋病毒/艾滋病的关键目标人群。 预防战略。虽然广泛中和抗体（bnAb）的诱导是HIV疫苗的主要目标， 然而，迄今为止测试的候选疫苗中没有一种能够产生这种反应。 值得注意的是，最近的研究表明，感染艾滋病毒的儿童更早地发展出广泛的中和作用， 比成年人更频繁。为了证实这些发现，我们最近比较了 在1-3岁HIV感染儿童的大型横断面队列中， 感染的成年人到一岁时，儿童的中和宽度与成人相当， 证实感染艾滋病毒的儿童能够早期发展广泛中和。有趣的是， 对于中和宽度通常由一种或两种特异性的bnAb介导的成人， 在大多数儿童中，中和似乎是由多克隆应答介导的。这表明 不同的机制可以驱动儿童和成人中和宽度的发展。 重要的是，最近的一项转录组分析揭示了一种蛋白质的表达与 调节HIV感染成人中自然杀伤（NK）细胞功能（RAB 11 FIP 5）和bnAb发育。 早期生命NK细胞在功能上不同于成人NK细胞;并且已经确定，早期生命NK细胞在功能上不同于成人NK细胞。 免疫环境与成人不同。然而，无论是独特的早期生命免疫环境还是 特异性因子如RAB 11 FIP 5的表达与早期广泛中和有关 幼儿的发展仍然未知。因此，在本研究中，我们建议检验假设 不同的宿主转录谱与HIV特异性抗体的产生有关， 早期生命中的中和宽度，使用登记的HIV感染儿童的存档纵向样本 在母婴队列研究（MICS）和NICHD国际研究中心发展倡议中， 儿科研究（NISDI）。我们的具体目标是：1）确定广泛的发展动力学 HIV感染儿童纵向队列中的中和作用;以及2）评估 HIV感染儿童的转录谱和中和宽度的发展。本研究将 加强我们目前对HIV感染者中和宽度发展动力学的理解， 儿童并提供有关导致中和宽度的分子途径的新见解 生命早期的发展。总之，这些新的信息将指导艾滋病毒疫苗的开发 旨在保护首次性行为之前的策略。此外，广泛的转录特征 中和可以作为早期识别免疫策略的标志物， 可能导致广泛中和。