Early Immune Development and Function in Neonates Exposed to Maternal HIV Infection

首席研究员/项目主任(最后、第一、中间)：徐焕斌！ 项目摘要/摘要 母亲感染艾滋病毒对怀孕期间感染婴儿具有很高的风险，易导致 婴儿对免疫的抗体反应和不良的健康结果，特别是在他们出生的第一年， 尽管大多数新生儿仍未被感染，这表明母亲感染艾滋病毒会对 早期免疫系统的发育和功能。在提案中，我们假设艾滋病毒感染在 妊娠通过持续的炎症信号和病理改变损害母婴沟通 胎盘，危害胎儿全身和淋巴组织的发育，以及随后的抗体 在生命早期对疫苗的反应。我们还假设，服用抑制性联合抗逆转录病毒 治疗(CART)可直接恢复胎儿免疫发育，改善婴儿免疫功能。vbl.使用 非人灵长类动物模型，我们发现了许多关于免疫学和 HIV的发病机制与灵长类新生儿免疫学。我们已经证明，感染SIV的婴儿迅速和 选择性地丢失粘膜固有淋巴样细胞(ILC1/NK，ILC3，ILC17，ILC22)和调节性T细胞，导致 生发中心(GC)反应功能障碍，随后抗体反应不足。我们最大的 最近的研究表明，正常情况下，GC B细胞在出生后几天内迅速聚集在毛囊中，高度协同 表达Ki67、Bcl6和EZH2。然而，这些EZH2 GC B细胞没有出现在SIV-1的淋巴结中。 感染的新生儿，伴有淋巴结构受损和抗体反应不足。研究 表明EZH2负责细胞周期蛋白依赖性激酶抑制物(CDK抑制物， 细胞周期抑制)通过组蛋白H3赖氨酸27(H3K27me3)的三甲基化。在这里，我们将调查 婴儿出生时抗体反应受损的细胞和分子机制 通过对新生儿和婴儿的粘膜和系统淋巴进行详细检查而感染SIV的母体 组织及其发育和功能。鉴于越来越多的数据表明，不断增长的艾滋病毒- 暴露型未感染(HEU)婴儿有免疫功能损害，显然有许多基本原因 我们对母亲感染艾滋病毒如何影响胎盘功能和胎儿免疫的认识存在差距 发育，以及为什么HEU婴儿有缺陷的抗体反应。这项提议旨在及早解决 暴露于母体艾滋病毒感染的新生儿的全身和淋巴系统发育：a) 测定胎盘免疫学变化；b)评估新生儿免疫发育和功能 母体艾滋病毒感染背景下的全身和淋巴隔间；以及；c)探索细胞 暴露在常规疫苗下的婴儿抗体应答受损的分子机制 对产妇HIV感染，孕期有无短期购物车。从这一过程中获得的知识 该提案将对优化艾滋病毒预防和改善免疫接种具有极其重要的意义 婴儿接触母体艾滋病毒感染时的治疗方案。

Principal Investigator/Program Director (Last, first, middle): Xu, Huanbin! PROJECT SUMMARY / ABSTRACT Maternal HIV infection poses high risks for infecting infants during pregnancy, predisposing abnormalities of antibody responses to immunization and poor health outcomes in infants, especially during their first year of life, albeit the majority of newborn infants remain uninfected, suggesting that maternal HIV infection compromises early immune system development and function. In proposal, we hypothesize that HIV infection during pregnancy impairs maternal/fetal communications through persistent inflammatory signals and pathological placenta, which compromise fetal development of systemic and lymphoid tissues, and subsequent antibody responses to vaccines in early-life. We also hypothesize that administering suppressive combined antiretroviral therapy (cART) may directly restore fetal immune development, and improve immune function in infants. Using non-human primate models, we have discovered many unexpected facts regarding the immunology and pathogenesis of HIV and primate neonatal immunology. We have shown that SIV-infected infants rapidly and selectively lose mucosal innate lymphoid cells (ILC1/NK, ILC3, ILC17, ILC22) and regulatory T cells resulting in dysfunctional germinal center (GC) reactions and subsequently, inadequate antibody responses. Our most recent studies show that normally, GC B cells, rapidly aggregate in follicles within days after birth, highly co- express Ki67, Bcl-6 and EZH2. However, these EZH2+ GC B cells do not appear in lymph nodes of SIV- infected neonates, accompanied by impaired lymphoid architecture and inadequate Ab responses. Studies indicate EZH2 is responsible for epigenetic silencing of the cyclin dependent kinase inhibitor (CDK inhibitor, cell cycle suppression) via trimethylation of histone H3 lysine 27 (H3K27me3). Here we will investigate the cellular and molecular mechanisms behind the impaired generation of antibody responses in infants born to SIV-infected dams through detailed examinations of neonatal and infant mucosal and systemic lymphoid tissues and their development and function. Given converging data that the growing populations of HIV- exposed uninfected (HEU) infants have immunologic impairments, it is clear that there are many fundamental gaps in our understanding of how maternal HIV infection may influence placental function, fetal immune development, and why HEU infants have defective Ab responses. This proposal is designed to address early development of systemic and lymphoid compartments in neonates exposed to maternal HIV infection: a) determining the alterations of placental immunology; b) evaluating neonatal immune development and function of systemic and lymphoid compartments in the context of maternal HIV infection, and; c) exploring the cellular and molecular mechanisms involved in compromised Ab responses to routine vaccinations in infants exposed to maternal HIV infection, with and without short-term cART during pregnancy. The knowledge gained in this proposal will be of tremendous importance for optimizing HIV prevention, and improving immunization regimens for infants when exposed to maternal HIV infection.