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.

首席调查员/计划总监（最后，第一，中间）：Xu，Huanbin！ 项目摘要 /摘要 孕产妇的艾滋病毒感染在怀孕期间对婴儿的感染构成高风险，易于异常 抗体对免疫的反应和婴儿的健康状况不佳，尤其是在生命的第一年， 尽管大多数新生婴儿仍未感染，这表明母亲的艾滋病毒感染损害了 早期免疫系统的开发和功能。在提案中，我们假设在 怀孕通过持续的炎症信号和病理损害产妇/胎儿通讯 胎盘，这会损害全身和淋巴组织的胎儿发育以及随后的抗体 对早期疫苗的反应。我们还假设给予抑制性抗逆转录病毒组合 治疗（CART）可以直接恢复胎儿免疫发育，并改善婴儿的免疫功能。使用 非人类灵长类动物模型，我们发现了许多有关免疫学和的意外事实 艾滋病毒和灵长类动物新生儿免疫学的发病机理。我们已经表明，SIV感染的婴儿迅速 有选择地失去粘膜先天淋巴样细胞（ILC1/NK，ILC3，ILC17，ILC22）和调节T细胞，导致导致的T细胞 功能失调的生发中心（GC）反应，随后，抗体反应不足。我们最大的 最近的研究表明，通常，GC B细胞在出生后几天内迅速聚集在卵泡中，高度共同 Express KI67，BCL-6和EZH2。但是，这些EZH2+ GC B细胞不出现在SIV-的淋巴结中 被感染的新生儿，伴随着淋巴结构受损和AB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的表观遗传沉默（CDK抑制剂， 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 婴儿出生的婴儿产生抗体反应受损后的细胞和分子机制 通过详细检查新生儿和婴儿粘膜和全身淋巴样的SIV感染大坝 组织及其发育和功能。鉴于收敛的数据，艾滋病毒种群不断增长 暴露于未感染的（HEU）婴儿有免疫障碍，很明显，有很多基本 我们对母体HIV感染如何影响胎盘功能，胎儿免疫的理解缺口 发展以及HEU婴儿为什么会有AB反应不良。该建议旨在提早解决 暴露于母体HIV感染的新生儿的全身和淋巴室的发展：a） 确定胎盘免疫学的改变； b）评估新生儿免疫发育和功能 在母亲艾滋病毒感染的背景下，全身和淋巴室的c）探索细胞 以及涉及违反AB的反应对常规疫苗接种的分子机制暴露的反应 在怀孕期间有和没有短期手推车的母亲艾滋病毒感染。在这方面获得的知识 提案对于优化预防艾滋病毒和改善免疫将非常重要 婴儿暴露于孕产妇HIV感染时的治疗方案。