HIV transcellular and transsynaptic penetration of mucosal epithelium

描述(由申请人提供)：粘膜上皮是HIV在感染过程中与人体接触的第一个组织部位，在决定其能否成功建立系统性感染方面发挥着关键作用。我们还发现，HIV穿透细胞的效率随粘膜上皮复层程度的不同而不同，也与抗HIV天然蛋白β-防御素2和3以及分泌性白细胞蛋白酶抑制物(SLPI)的表达水平有关。我们已经证明，HIV通过粘膜上皮细胞的传播可以通过跨细胞传播，也可以通过跨突触穿透在上皮细胞之间传播。通过跨突触传递从上皮细胞传播到免疫细胞，可能会导致全身性艾滋病毒感染。通过成人粘膜上皮，如宫颈上皮，以及通过胎儿/新生儿口腔或肠道上皮传播仍然是重要的临床问题。目前没有疫苗可用于减少艾滋病毒的传播，其他预防方法，如对暴露于病毒的个人进行抗逆转录病毒治疗，可能不起作用，因为跨细胞或跨突触传播都不需要病毒复制或病毒膜与细胞膜的融合。迫切需要新的方法来减少HIV通过粘膜上皮的传播，但要开发这些方法，更好地了解HIV跨上皮细胞和跨突触传播的分子机制是至关重要的。因此，这项建议的具体目的是：(1)确定HIV通过粘膜上皮跨细胞和跨突触传播的机制；(2)确定上皮性抗HIV固有蛋白在HIV跨粘膜上皮传播中的作用。从这项提议中获得的数据将极大地促进目前对HV通过粘膜上皮传播机制的了解，并将为设计专门阻断HIV通过这些上皮细胞的药物开辟新的途径。 公共卫生相关性：通过粘膜上皮传播艾滋病毒是确定艾滋病毒感染的关键初始步骤之一，但这一过程仍然知之甚少。这项研究将描述艾滋病毒通过上皮细胞感染免疫细胞的不同方式，以及上皮细胞用于灭活艾滋病毒的各种防御措施。从这些研究中获得的知识可能会导致开发预防艾滋病毒感染的新方法。

DESCRIPTION (provided by applicant): Mucosal epithelia are the first tissue sites of contact of HIV with the human body during the course of infection, and these play a critical role in determining its success in establishing systemic infection. We have also shown that the efficiency of transcytotic penetration by HIV varies with the degree of stratification of the mucosal epithelium, as well as with the levels of expression of the anti-HIV innate proteins beta-defensin 2 and 3, and secretory leukocyte protease inhibitor (SLPI). We have shown that HIV transmission through mucosal epithelial cells can occur by transcytotic and between epithelial cells by transsynaptic penetration. Spread from epithelial cells to immune cells by transsynaptic transmission may then lead to systemic HIV infection. Transmission through adult mucosal epithelium such as that of the cervix, and across fetal/neonatal oral or intestinal epithelium remain important clinical problems. There are currently no vaccines available to reduce HIV transmission and other preventive approaches such as administering antiretroviral therapy to exposed individuals may not work since neither transcytosis nor transsynaptic transmission require viral replication or fusion of viral membranes with cellular membranes. New methods to reduce HIV transmission across mucosal epithelia are urgently needed, but to develop these methods, a better understanding of the molecular mechanisms of HIV transcytotic and transsynaptic transmission across epithelial surfaces is critical. Accordingly, the specific aims of this proposal are: (1) To determine the mechanisms of transcytotic and transsynaptic spread of HIV through mucosal epithelia; (2) To determine the role of epithelial anti-HIV innate proteins in HIV transmission across mucosal epithelia. The data obtained from this proposal will greatly advance current knowledge about the mechanisms of HV transmission across mucosal epithelia and will open new avenues for designing drugs that may specifically block HIV passage across these epithelia. PUBLIC HEALTH RELEVANCE: HIV transmission via mucosal epithelium is one of the key initial steps in establishing HIV infection but this process remains poorly understood. This study will characterize the different ways used by HIV to pass through epithelium to infect immune cells, and the various defenses used by epithelial cells to inactivate HIV. Knowledge obtained from these studies may lead to the development of new approaches to prevent HIV infection.