Role of oral herpesvirus microbiota in pathogenesis of HIV mother to child transmission

口腔疱疹病毒微生物群在艾滋病毒母婴传播发病机制中的作用

基本信息

批准号：
10172885
负责人：
SHAROF M TUGIZOV
金额：
$ 52.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-06 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172885
关键词：
Actins Adult Anti-Retroviral Agents Antiviral Agents Apical Binding Blood Platelets CCL2 gene CD4 Positive T Lymphocytes Calcium Cell membrane Cells Cytomegalovirus Cytomegalovirus Infections Cytoskeleton Dendritic Cells Development Docking Endosomes Epithelial Epithelial Cells Exocytosis Fetus Glycoproteins Goals Growth Factor HIV HIV tat Protein Herpesviridae Herpesvirus 1 Human Human Herpesvirus 4 Immune Infant Interferon Type II Investigation Knowledge LMP1 Lead Mediating Molecular Mother-to-child HIV transmission Mothers Mucous Membrane Multivesicular Body Neonatal Oral Oral mucous membrane structure Pathogenesis Pathway interactions Peptidoglycan Perinatal Peripheral Blood Mononuclear Cell Prevention strategy Preventive Prophylactic treatment Proteins Publishing RANTES Reporting Role Signal Transduction Simplexvirus Surface T-Lymphocyte TNF gene Therapeutic Tight Junctions Tonsil Vacuole Vertical Disease Transmission Virion Virus Virus Diseases Work base beta-Defensins chemokine experimental study fetal intraepithelial late endosome macrophage microbiota neonate novel therapeutic intervention oral HIV oral cavity epithelium oral microbial community oral microbiome prevent rab GTP-Binding Proteins receptor transmission process virtual virus envelope

项目摘要

Project Summary/Abstract Approximately 250,000 infants acquire human immunodeficiency virus (HIV-1) infection annually despite antiretroviral prophylaxis, suggesting the need for alternative prevention strategies. Mother-to-child transmission (MTCT) is an important pathway for the spread of HIV from mother to fetus and infant; however, the molecular mechanisms of HIV MTCT are poorly understood. Our recent work showed that >90% of virions internalized into infant tonsil epithelium are sequestered in the endosomes, including multivesicular bodies (MVBs) and vacuoles of epithelial cells, for up to 9 days. In contrast, such prolonged intracellular sequestration of HIV was not observed in adult tonsil epithelial cells: intracellular virus was rapidly inactivated. This is consistent with our published work showing that intracellular HIV is inactivated in adult polarized epithelial cells by high-level expression of anti-HIV innate immune proteins human beta defensin 2 (HBD2) and HBD3. However, fetal and infant oral epithelial cells did not express HBDs, leading to transmission of infectious HIV. In ongoing experiments we have found that the interaction of herpes simplex virus-1 (HSV-1), human cytomegalovirus (HCMV), and Epstein-Barr virus (EBV) with the apical (mucosal) surface of infant tonsil epithelial cells containing HIV-1 leads to the exocytosis of HIV virions, which are infectious for peripheral blood mononuclear cells (PBMCs). HSV, HCMV, and EBV are oral microbiota of infants, and their interaction with infant tonsil epithelial cells containing HIV may lead to the release and spread of HIV into CD4+ T lymphocytes, macrophages, and Langerhans/dendritic cells (LCs/DCs), leading to HIV MTCT. Virtually nothing is known about the role of herpesvirus oral microbiota in HIV MTCT. Therefore, investigation of the molecular mechanisms underlying HSV-, HCMV-, and EBV-associated HIV spread from neonatal/infant oral epithelia into HIV-susceptible cells will undoubtedly lead to a better understanding of the oral microbiota-associated pathogenesis of HIV MTCT and the development of a new preventive therapeutic strategy against perinatal viral infection. Accordingly, the specific aims of this proposal are (1) To study the molecular mechanisms of HSV-, HCMV-, and EBV-induced HIV exocytosis in infant tonsil epithelium containing sequestered HIV; (2) To investigate the role of HSV, HCMV, and EBV in HIV MTCT through disruption of mucosal epithelium and activation of HIV-susceptible cells; and (3) To study the potential mechanisms of intravesicular HIV inactivation by antiviral innate immune proteins human beta defensin 2 (HBD2) and HBD3. This work will greatly advance knowledge of the role of herpesvirus oral microbiota in the pathogenesis of HIV MTCT. The proposed studies may lead to the establishment of new therapeutic approaches based on inhibition or reduction of herpesvirus- associated HIV spread from mucosal epithelial cells into HIV target cells and elimination of intraepithelial reservoirs, which in turn may reduce HIV MTCT.

项目概要/摘要每年约有 250,000 名婴儿感染人类免疫缺陷病毒 (HIV-1)，尽管抗逆转录病毒预防，表明需要替代预防策略。母婴传播（MTCT）是艾滋病毒从母亲传播到胎儿和婴儿的重要途径；然而， HIV 母婴传播的分子机制尚不清楚。我们最近的工作表明 >90% 的病毒粒子内化到婴儿扁桃体上皮中并被隔离在内涵体中，包括多泡体 (MVB) 和上皮细胞液泡，持续长达 9 天。相反，这种长期的细胞内隔离在成人扁桃体上皮细胞中未观察到 HIV 病毒：细胞内病毒迅速失活。这是与我们发表的研究一致，表明细胞内 HIV 在成人极化上皮细胞中失活通过高水平表达抗 HIV 先天免疫蛋白人 β 防御素 2 (HBD2) 和 HBD3。然而，胎儿和婴儿口腔上皮细胞不表达HBD，从而导致传染性HIV的传播。在正在进行的实验中，我们发现单纯疱疹病毒 1 (HSV-1) 与人类的相互作用婴儿扁桃体顶（粘膜）表面的巨细胞病毒（HCMV）和 Epstein-Barr 病毒（EBV）含有 HIV-1 的上皮细胞会导致 HIV 病毒颗粒的胞吐作用，从而对外周血具有传染性单核细胞（PBMC）。 HSV、HCMV 和 EBV 是婴儿的口腔微生物群，它们与含有HIV的婴儿扁桃体上皮细胞可能导致HIV释放并扩散到CD4+ T中淋巴细胞、巨噬细胞和朗格汉斯细胞/树突状细胞 (LC/DC)，导致 HIV 母婴传播。几乎什么都没有人们了解疱疹病毒口腔微生物群在 HIV 母婴传播中的作用。因此，分子研究 HSV、HCMV 和 EBV 相关 HIV 从新生儿/婴儿口腔上皮传播至 HIV 易感细胞无疑将有助于更好地了解口腔微生物群相关的 HIV母婴传播的发病机制及围产期预防治疗新策略的开发病毒感染。因此，本提案的具体目标是（1）研究其分子机制。 HSV、HCMV 和 EBV 诱导的婴儿扁桃体上皮中含有隔离的 HIV 的 HIV 胞吐作用； (2) 至研究 HSV、HCMV 和 EBV 通过破坏粘膜上皮在 HIV 母婴传播中的作用激活艾滋病毒易感细胞； (3) 研究囊泡内HIV灭活的潜在机制通过抗病毒先天免疫蛋白人类β防御素2 (HBD2) 和HBD3。这项工作将大大推进了解疱疹病毒口腔微生物群在 HIV 母婴传播发病机制中的作用。拟议的研究可能导致基于抑制或减少疱疹病毒的新治疗方法的建立相关的 HIV 从粘膜上皮细胞扩散到 HIV 靶细胞并消除上皮内储存库，这反过来又可能减少艾滋病毒母婴传播。