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

首席研究员/项目负责人（末、中、一）：徐焕斌！ 项目总结/摘要 母亲感染艾滋病毒对怀孕期间感染婴儿的风险很高， 对免疫的抗体反应和婴儿的不良健康结果，特别是在他们生命的第一年， 尽管大多数新生儿仍然没有感染，但这表明母亲感染艾滋病毒会损害 早期免疫系统的发育和功能。在建议中，我们假设， 妊娠通过持续的炎症信号和病理性的 胎盘，其损害全身和淋巴组织的胎儿发育，以及随后的抗体 对疫苗的反应。我们还假设给予抑制性联合抗逆转录病毒药物 抗逆转录病毒治疗（cART）可以直接恢复胎儿的免疫发育，并改善婴儿的免疫功能。使用 在非人类灵长类动物模型中，我们发现了许多关于免疫学的意想不到的事实， HIV的发病机制和灵长类新生儿免疫学。我们已经证明，SIV感染的婴儿迅速， 选择性丧失粘膜固有淋巴样细胞（ILC 1/NK、ILC 3、ILC 17、ILC 22）和调节性T细胞， 功能失调的生发中心（GC）反应和随后的抗体应答不足。我们最 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卵泡中， 表达Ki 67、Bcl-6和EZH 2。然而，这些EZH 2 + GC B细胞并不出现在SIV-1的淋巴结中。 感染的新生儿，伴随着受损的淋巴结构和抗体反应不足。研究 表明EZH 2负责细胞周期蛋白依赖性激酶抑制剂（CDK抑制剂， 细胞周期抑制）通过组蛋白H3赖氨酸27（H3 K27 me 3）的三甲基化。在这里，我们将调查 婴儿出生后抗体反应产生受损的细胞和分子机制 通过详细检查新生儿和婴儿粘膜和全身淋巴组织， 组织及其发育和功能。有数据表明艾滋病病毒感染人数的增长- 暴露未感染（HEU）的婴儿有免疫损伤，很明显，有许多基本的 我们对母体艾滋病毒感染如何影响胎盘功能、胎儿免疫功能 高浓缩铀婴儿抗体反应缺陷的原因。该提案旨在尽早解决 暴露于母体HIV感染的新生儿的全身和淋巴区室的发育：a） 确定胎盘免疫学的改变; B）评估新生儿免疫发育和功能 在母体HIV感染的背景下，系统和淋巴区室的变化，以及; c）探索细胞 暴露于常规疫苗的婴儿中抗体应答受损的分子机制 孕妇感染艾滋病毒，在怀孕期间有和没有短期cART。在此过程中获得的知识 该提案对于优化艾滋病毒预防和提高免疫接种水平具有极其重要的意义 婴儿暴露于母亲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.