Molecular mechanisms of oral HIV transmission modeling MTCT

描述（由申请人提供）：人类免疫缺陷病毒（艾滋病毒）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。在没有干预的情况下，MTCT的成功率可达35%。抗逆转录病毒疗法（ART）显著降低了MTCT的发病率；然而，这种治疗在发展中国家并不普遍，而且抗逆转录病毒疗法并不影响病毒通过上皮的最初传播。要引起全身感染，HIV必须首先通过新生儿/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通过新生儿/婴儿粘膜上皮传播的机制尚不清楚。我们已经开发了两种新的互补模型来研究HIV的上皮传播：单层极化口腔上皮细胞和极化取向的成人和胎儿/婴儿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HIV传播可能通过胎儿/婴儿的口腔上皮发生，而不是通过成人的口腔上皮。我们的初步数据表明，hiv相关磷脂酰丝氨酸（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新生儿/婴儿口腔粘膜上皮的无细胞病毒胞吞作用。来自母亲宫颈/阴道液和母乳的hiv感染细胞可通过巨噬细胞/淋巴细胞粘附分子与粘膜上皮的相互作用渗入新生儿粘膜上皮。我们还发现，抗hiv先天蛋白HBD-2和- 3通过与gp120的间接相互作用，在病毒在囊泡室的胞吞过程中灭活病毒。研究HIV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HIV MTCT的发病机制，并开发新的HIV MTCT预防治疗策略。因此，这项建议的具体目的是：研究HIV巨噬细胞和内吞作用在病毒在胎儿/婴儿口腔和肠上皮间传播中的作用。2. 目的：研究hiv感染巨噬细胞渗入胎儿/婴儿口腔和肠道上皮的分子机制。3. 探讨HBD-2和-3介导的HIV在胎儿/婴儿口腔和肠道上皮细胞内失活的机制。这些研究结果将为HIV通过胎儿/新生儿口腔和肠道粘膜上皮MTCT的分子机制提供新的信息，并为设计特异性阻断HIV通过粘膜上皮MTCT的抗病毒药物开辟新的途径。

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.