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

• 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
• 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

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.

项目摘要/摘要 尽管 抗逆转录病毒预防，表明需要替代预防策略。母子 传播（MTCT）是艾滋病毒从母亲到胎儿和婴儿传播的重要途径。然而， HIV MTCT的分子机制知之甚少。我们最近的工作表明，> 90％的病毒体 内部化成扁桃体上皮的内体被隔离在内体中，包括多尖体体 （MVB）和上皮细胞的液泡，长达9天。相反，如此延长的细胞内螯合 在成年扁桃体上皮细胞中未观察到HIV：细胞内病毒迅速失活。这是 与我们发表的工作一致，表明细胞内HIV在成人极化上皮细胞中被灭活 通过抗HIV先天性免疫蛋白人β防御素2（HBD2）和HBD3的高级表达。 然而，胎儿和婴儿口服上皮细胞没有表达HBD，导致感染性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）的相互作用，人类 巨细胞病毒（HCMV）和Epstein-Barr病毒（EBV），具有扁桃体的顶端（粘膜）表面 含有HIV-1的上皮细胞会导致HIV病毒体的胞吐作用，这对外周血具有感染性 单核细胞（PBMC）。 HSV，HCMV和EBV是婴儿的口服微生物群，它们与 婴儿扁桃体上皮细胞含有HIV可能导致HIV释放和扩散到CD4+ T中 淋巴细胞，巨噬细胞和Langerhans/树突状细胞（LCS/DC），导致HIV MTCT。几乎什么都没有 关于疱疹病毒口服微生物群在HIV MTCT中的作用已知。因此，研究分子 HSV-，HCMV和EBV相关的HIV的基础机制从新生儿/婴儿口服上皮扩散到 艾滋病毒敏感细胞无疑会更好地理解口服微生物群相关的 HIV MTCT的发病机理以及针对围产期的新预防治疗策略的发展 病毒感染。因此，该提案的具体目的是（1）研究分子机制 HSV-，HCMV和EBV诱导的含有隔离HIV的婴儿扁桃体上皮的HIV胞毒性； （2）至 通过粘膜上皮的破坏和 艾滋病毒敏感细胞的激活； （3）研究内部HIV失活的潜在机制 通过抗病毒先天免疫蛋白人β防御素2（HBD2）和HBD3。这项工作将大大推动 对疱疹病毒口服微生物群在HIV MTCT发病机理中的作用的了解。提出的研究 可能导致建立基于抑制或减少疱疹病毒的新治疗方法 相关的HIV从粘膜上皮细胞扩散到HIV靶细胞并消除上皮内。 储层，进而可以减少HIV MTCT。