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

暴露于母亲 HIV 感染的新生儿的早期免疫发育和功能

• 批准号: 9973205
• 负责人: Huanbin Xu
• 金额: $ 50.47万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973205
• 关键词: AIDS prevention; Address; Adult; Anatomy; Antibody Formation; Antibody Response; Antigens; Architecture; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Birth; Caring; Cell Cycle; Cells; Childhood Acute Lymphocytic Leukemia; Chronic; Communication; Cyclin-Dependent Kinase Inhibitor; Data; Development; EZH2 gene; Environment; Epigenetic Process; Event; Exposure to; Fetal Development; Frequencies; Gene Silencing; Generations; HIV; HIV Infections; HIV-exposed uninfected infant; Health; Helper-Inducer T-Lymphocyte; Hepatitis B Virus; Histone H3; Histopathology; Immune; Immune System Diseases; Immune system; Immunization; Immunization Schedule; Immunologics; Immunology; Impairment; Infant; Infection; Inflammation Mediators; Inflammatory; Influenza vaccination; Intervention; Knowledge; Leukocytes; Life; Liquid substance; Lymphoid; Lymphoid Cell; Lymphoid Tissue; Lysine; Macaca; Maternal-Fetal Exchange; Measures; Modeling; Molecular; Mothers; Mucous Membrane; Myelogenous; Myeloid Cells; Natural Immunity; Neonatal; Newborn Infant; Outcome; Pathogenesis; Pathologic; Placenta; Plasma; Play; Population; Pregnancy; Prevention; Primates; Principal Investigator; Reaction; Regimen; Regulatory T-Lymphocyte; Reporting; Role; SIV; Signal Transduction; Sterility; Structure; Structure of germinal center of lymph node; Systems Development; Tissues; Uterus; Vaccination; Vaccines; Viral Load result; Viral reservoir; adaptive immunity; antiretroviral therapy; comparative; cytokine; design; fetal; fetal programming; high risk; immune function; improved; inhibitor/antagonist; lymph nodes; neonatal infection; neonate; nonhuman primate; pathogen; prenatal exposure; programs; response

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.

首席研究员/项目主任（后、一、中）：徐焕斌！ 项目概要/摘要 母亲感染艾滋病毒会在怀孕期间感染婴儿，从而导致婴儿出现异常的风险很高。 婴儿对免疫接种的抗体反应和不良健康结果，特别是在婴儿出生的第一年， 尽管大多数新生儿仍未感染，这表明孕产妇感染艾滋病毒会损害健康 早期免疫系统的发育和功能。在提案中，我们假设 HIV 感染期间 妊娠通过持续的炎症信号和病理学损害母体/胎儿的沟通 胎盘，会损害胎儿全身和淋巴组织的发育，以及随后的抗体 生命早期对疫苗的反应。我们还假设联合使用抑制性抗逆转录病毒药物 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和免疫学方面意想不到的事实 HIV 的发病机制和灵长类新生儿免疫学。我们已经证明，感染 SIV 的婴儿会迅速且 选择性丢失粘膜先天淋巴细胞（ILC1/NK、ILC3、ILC17、ILC22）和调节性 T 细胞，从而导致 生发中心（GC）反应功能失调，随后抗体反应不足。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在卵泡中迅速聚集，高度协同 表达 Ki67、Bcl-6 和 EZH2。然而，这些 EZH2+ GC B 细胞不会出现在 SIV- 的淋巴结中。 受感染的新生儿，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剂（CDK 抑制剂， 通过组蛋白 H3 赖氨酸 27 (H3K27me3) 的三甲基化来抑制细胞周期。在这里我们将调查 出生的婴儿抗体反应受损背后的细胞和分子机制 通过对新生儿和婴儿粘膜和全身淋巴进行详细检查来发现 SIV 感染的母鼠 组织及其发育和功能。鉴于不断增长的艾滋病毒感染者人数的综合数据 暴露的未感染（HEU）婴儿有免疫损伤，很明显有许多基本因素 我们对孕产妇艾滋病毒感染如何影响胎盘功能、胎儿免疫的理解存在差距 发育，以及为什么 HEU 婴儿的抗体反应有缺陷。该提案旨在尽早解决 暴露于母体 HIV 感染的新生儿全身和淋巴室的发育：a) 确定胎盘免疫学的改变； b) 评估新生儿免疫发育和功能 孕产妇艾滋病毒感染情况下的全身和淋巴区室； c) 探索细胞 暴露的婴儿对常规疫苗接种的抗体反应受损所涉及的分子机制 孕期接受或不接受短期 cART 治疗对孕产妇 HIV 感染的影响。在这过程中获得的知识 该提案对于优化艾滋病毒预防和改善免疫接种具有极其重要的意义 接触母亲艾滋病毒感染的婴儿的治疗方案。