Role of Oral Epithelial Cells in HIV-1 Transmission

抗HIV-1感染的第一道防线及其传播的主要部位是口腔和生殖器的粘膜表面以及胃肠道。艾滋病毒-1通过口腔传播的比率大大低于通过生殖器或肠道途径传播的比率，尽管它仍然具有风险。为了解决对HIV-1感染的口腔抗性或易感性的问题，本申请集中于降低口腔中传播率的细胞因子。具体而言，我们建议： 1.确定口腔上皮细胞是否比生殖器或直肠上皮细胞更不能将HIV-1从感染的固有层细胞转移到口腔分泌物中。为了实现这一目标，将招募大约50名主要是HIV-1感染的成年人，他们没有服用抗逆转录病毒药物，并被要求捐献唾液、肠道、宫颈阴道或精液和外周血。将在同一个体中确定唾液与生殖器或直肠分泌物中释放的HIV-1之间的差异，具体涉及：a）游离病毒和细胞相关病毒的水平; B）其产生生产性感染的能力; c）感染性病毒的表型（X4或R5），以及含有HIV-1的细胞类型。 2.确定口腔上皮细胞上HIV-1受体和辅助受体以及相关粘附分子的表达是否导致它们在将HIV-1从根尖表面转移到上皮下靶细胞方面不如生殖器或直肠上皮细胞有效。将在口腔、直肠和生殖器来源的外植体组织上确定CD 4、GaI-Cer、CCR 5、CXCR 4、ICAM-2和ICAM-3表达的差异以及HIV-1靶细胞的分布。此外，将确定上皮细胞选择性转运/被感染和产生游离或细胞相关形式的HIV-1表型的生产性感染的潜力。最后，通过上皮细胞系，将确定从口腔上皮细胞释放的游离HIV-1受体和辅助受体是否可以阻止HIV-1接近其靶细胞。 所产生的数据将有助于了解粘膜HIV-1传播。

The first line of defense against HIV-1 infections and the primary site for their transmission are mucosal surfaces of the oral cavity and the genital, and gastrointestinal tracts. The rate of HIV-1 transmission through oral cavity is significantly lower than the transmission through the genital or intestinal routes, although it still carries a risk. To address the question of oral resistance or susceptibility to HIV-l-infection, this application focuses on the cellular factors that reduce the transmission rate in oral cavity. Specifically, we propose to: 1. Establish whether oral epithelia are less capable of transferring HIV-1 from infected lamina propria cells into oral secretions than the genital or rectal epithelia. To accomplish this aim, approximately 50, primarily HIV-1 infected adults, not taking ART medication will be enrolled and asked to donate saliva, intestinal, cervicovaginal or seminal fluids and peripheral blood. Differences occurring between the HIV-1 released in saliva vs. the genital or rectal secretions, will be determined in the same individual with respect to: a) levels of free and cell-associated virus; b) its capacity to generate a productive infection; c) phenotype(s) (X4 or R5) of infectious viruses, and type of cells containing HIV-I. 2. Determine whether the expression of HIV-1 receptors and co-receptors and of relevant adhesion molecules on oral epithelia causes them to be less effective than the genital or rectal epithelia in transferring HIV-lfrom the apical surface to the subepithelial target cells. Differences in CD4, GaI-Cer, CCR5, CXCR4, ICAM-2 and ICAM-3 expression and the distribution of HIV-1 target cells will be ascertained on explant tissues of oral, rectal and genital origin. Moreover, their potential of epithelia to selectively transport/be infected and generate a productive infection by HIV-1 phenotypes in free or cell-associated forms will be determined. Finally, by means of epithelial cell lines, it will be established whether the free HIV-1 receptors and co-receptors released from the oral epithelial cells can prevent the access of HIV-1 to its target cells. The data generated will contribute to the understanding of mucosal HIV-1 transmission.