Molecular mechanisms of oral HIV transmission modeling MTCT

HIV口腔传播模型MTCT的分子机制

基本信息

批准号：
9222002
负责人：
SHAROF M TUGIZOV
金额：
$ 44.78万
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：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222002
关键词：
Adhesions Adult Antiviral Agents Binding Biological Models CCL2 gene CD4 Positive T Lymphocytes Cell Adhesion Molecules Cells Cervical Data Dendritic Cells Developing Countries Development Endocytosis Epithelial Epithelial Cells Epithelium Experimental Models Female of child bearing age Galactosylceramides HIV HIV Envelope Protein gp120 HIV Infections Heparan Sulfate Proteoglycan Human Human Milk Immune Immunoglobulins Incidence Infant Intercellular adhesion molecule 1 Intervention Intestines Investigation Knowledge Lead Lymphocyte Lymphocyte Function-Associated Antigen-1 Mediating Modeling Molecular Monocyte Chemoattractant Protein-1 Mother-to-child HIV transmission Mothers Mucins Neonatal Oral Oral mucous membrane structure Organ Oropharyngeal Pathogenesis Pathway interactions Penetration Phosphatidylserines Preventive Process Proteins Recombinants Role Satellite Viruses Signal Transduction Stratification Study models Surface Systemic infection T-Cell Receptor TNF gene Therapeutic Tissue Model Tissues Vertical Disease Transmission Viral Virion Virus antiretroviral therapy basolateral membrane beta-Defensins density design fetal intestinal epithelium macrophage migration monocyte neonate novel novel strategies oral HIV oral cavity epithelium phosphatidylserine receptor prevent protective effect public health relevance transcytosis transmission process vaginal fluid viral transmission

项目摘要

DESCRIPTION (provided by applicant): The global spread of Human Immunodeficiency Virus (HIV) infection in women of childbearing age has resulted in a substantial increase in mother-to-child transmission (MTCT) of HIV. In the absence of intervention, the rate of MTCT can reach 35%. Antiretroviral therapy (ART) has significantly reduced the incidence of MTCT; however, such treatment is not widely available in developing countries, and ART does not affect the initial transmission of the virus through the epithelium. To initiate systemic infection, HIV must first be transmitted across oropharyngeal and/or intestinal mucosal epithelia of neonates/infants and then infect susceptible immune cells, but the mechanisms of HIV transmission across neonatal/infant mucosal epithelia is poorly understood. We have developed two novel and complementary models for the study of epithelial transmission of HIV: monostratified polarized oral epithelial cells and polarized oriented oral and intestinal tissue explants of adult and fetal/infant origins. We have shown that cell-free and cell-associated HIV transmission may occur through the fetal/infant oral epithelium but not the adult oral epithelium. Our preliminary data show that HIV-associated phosphatidylserine (PS) interaction with the PS receptor T-cell immunoglobulin and mucin domain 1 (TIM-1) may facilitate cell-free viral transcytosis through the neonatal/infant oral mucosal epithelium. HIV-infected cells of the mother from cervical/vaginal fluid and breast milk may penetrate into neonatal mucosal epithelium by interaction of adhesion molecules of macrophages/lymphocytes with mucosal epithelia. We also found that the anti-HIV innate proteins HBD-2 and - 3 inactivate virus during its transcytosis in the vesicular compartment through indirect interaction with gp120. Investigation of the molecular mechanisms of HIV transmission via neonatal/infant oral and intestinal epithelia may lead to a better understanding of the pathogenesis of HIV MTCT and the development of a new preventive therapeutic strategy against HIV MTCT. Accordingly, the specific aims of this proposal are: 1. To study the role of HIV macropinocytosis and endocytosis in viral transmission across fetal/infant oral and intestinal epithelia. 2. To study the molecular mechanism of HIV-infected macrophage penetration into fetal/infant oral and intestinal epithelia. 3. To investigate the mechanisms of HBD-2- and -3-mediated intracellular inactivation of HIV in fetal/infant oral and intestinal epithelia. The results of these studies will provide new information on the molecular mechanisms of MTCT of HIV via fetal/neonatal oral and intestinal mucosal epithelia and will open new avenues for designing antiviral drugs that specifically block HIV MTCT through mucosal epithelia.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染在育龄妇女中的全球传播导致艾滋病毒母婴传播（MTCT）大幅增加。在不进行干预的情况下，母婴传播的发生率可达35%。抗逆转录病毒治疗（ART）显着降低了母婴传播的发生率；然而，这种治疗在发展中国家并未广泛普及，而且抗逆转录病毒治疗并不影响病毒通过上皮的初始传播。为了引发全身感染，HIV必须首先穿过新生儿/婴儿的口咽和/或肠粘膜上皮传播，然后感染易感免疫细胞，但HIV穿过新生儿/婴儿粘膜上皮传播的机制尚不清楚。我们开发了两种新颖且互补的模型来研究艾滋病毒的上皮传播：单层极化口腔上皮细胞和成人和胎儿/婴儿来源的极化定向口腔和肠道组织外植体。我们已经证明，无细胞和细胞相关的艾滋病毒传播可能通过胎儿/婴儿口腔上皮发生，但不会通过成人口腔上皮发生。我们的初步数据表明，HIV 相关的磷脂酰丝氨酸 (PS) 与 PS 受体 T 细胞免疫球蛋白和粘蛋白结构域 1 (TIM-1) 的相互作用可能促进通过新生儿/婴儿口腔粘膜上皮的无细胞病毒转胞吞作用。来自宫颈/阴道液和母乳的母亲的 HIV 感染细胞可能通过巨噬细胞/淋巴细胞粘附分子与粘膜上皮的相互作用渗透到新生儿粘膜上皮中。我们还发现，抗 HIV 固有蛋白 HBD-2 和 - 3 在病毒在囊泡区室中转胞吞过程中通过与 gp120 间接相互作用来灭活病毒。研究艾滋病毒通过新生儿/婴儿口腔和肠道上皮传播的分子机制可能有助于更好地了解艾滋病毒母婴传播的发病机制，并开发针对艾滋病毒母婴传播的新预防治疗策略。因此，本提案的具体目标是： 1. 研究 HIV 巨胞饮作用和内吞作用在胎儿/婴儿口腔和肠上皮病毒传播中的作用。 2. 研究HIV感染巨噬细胞渗透胎儿/婴儿口腔和肠上皮的分子机制。 3. 探讨HBD-2和HBD-3介导的胎儿/婴儿口腔和肠上皮细胞内HIV灭活的机制。这些研究的结果将提供关于通过胎儿/新生儿口腔和肠粘膜上皮进行艾滋病毒母婴传播的分子机制的新信息，并将为设计通过粘膜上皮特异性阻断艾滋病毒母婴传播的抗病毒药物开辟新途径。