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，在确定其是否成功建立全身感染方面起着关键作用。我们还表明，HIV的细胞渗透效率随粘膜上皮的分层程度以及抗HIV先天蛋白β -防御素2和3以及分泌性白细胞蛋白酶抑制剂（SLPI）的表达水平而变化。我们已经证明，HIV通过粘膜上皮细胞的传播可以通过胞吞发生，也可以通过跨突触渗透在上皮细胞之间发生。通过突触传递从上皮细胞扩散到免疫细胞可能导致全身性HIV感染。通过成人粘膜上皮（如子宫颈粘膜上皮）以及通过胎儿/新生儿口腔或肠上皮的传播仍然是重要的临床问题。目前还没有疫苗可以减少艾滋病毒的传播，其他预防方法，如对接触者进行抗逆转录病毒治疗可能不起作用，因为胞饮作用和跨突触传播都不需要病毒复制或病毒膜与细胞膜融合。迫切需要新的方法来减少艾滋病毒在粘膜上皮上的传播，但是为了开发这些方法，更好地了解艾滋病毒在上皮表面的经细胞和经突触传播的分子机制是至关重要的。因此，本提案的具体目的是：(1)确定HIV通过粘膜上皮的经细胞和经突触传播的机制；(2)确定上皮抗HIV先天蛋白在HIV跨粘膜上皮传播中的作用。从该提案中获得的数据将极大地推进目前关于艾滋病毒通过粘膜上皮传播机制的知识，并将为设计可能特异性阻断艾滋病毒通过这些上皮的药物开辟新的途径。

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.