PATHOGENESIS OF ORAL HAIRY LEUKOPLAKIA

描述：口腔毛状白斑的发展是EB病毒的结果。 HIV感染过程中口腔上皮细胞的感染。特定辅因子 增强口腔上皮细胞对感染的易感性(不足 或不适当的免疫反应)和/或延长受感染病毒的存活时间 细胞(与转化病毒合并感染，免疫反应不足)。 以深入了解决定EBV如何感染上皮细胞的事件 细胞，并加深我们对OHL发病机制的理解。 提案中的步骤：检验细胞培养系统的假设 将建立由EBV直接裂解感染或有效的 潜伏感染后可出现溶血性感染 在上皮细胞中。 具体目标是：1)分析永生化的、非致瘤的上皮细胞 自然表达病毒受体并能稳定表达的细胞系 用重组EBV选择感染。探索受体是如何 调节依附、内化和信号传递，并决定哪些基因 在进入时表示。比较不同病毒株感染病毒的能力 产生有效的感染并评估早期感染是否有溶解作用 组件。确定是否可以通过以下方式激活早期溶血复制 特定的细胞因子(在HIV感染中可能会改变)，并将进行研究 导致从建立的潜在程序切换的事件 重组病毒的体外筛选到已裂解的方案 体内观察(分化诱导物、即刻早期基因 转移、癌基因表达拮抗剂)。 2)应用观察建立正常的上皮细胞 文化体系。获得舌侧来源的正常口腔角质形成细胞， 这个部位的角质形成细胞被改造成表达HPV 16E6和/或E7 从这个部位自然地产生癌前病变和完全恶性。这些 将检查细胞的受体表达、感染性和 他们能够支持两种类型的常规EBV感染 培养系统以及器官类型培养。暴露的影响 细胞转化为炎症介质(在HIV感染中可能发生改变) 将根据受体的表达和病毒的模式进行评估 感染。 3)研究上皮系中特定的裂解病毒基因的生物学和 口腔角质形成细胞在培养中。初步研究将集中在眼前的 早期的反式激活剂。这些基因将由逆转录病毒导入 可诱导启动子控制下的基因转移及其机制 在不存在的情况下改变细胞分化状态的能力 EBV感染和特异性炎症介质的存在 将会被评估。

DESCRIPTION: The development of oral hairy leukoplakia is a result of EBV infection in oral epithelial cells during HIV infection. Specific cofactors enhance the susceptibility of oral epithelial cells to infection (inadequate or inappropriate immune responses) and/or prolong survival of virus infected cells (coinfection with transforming viruses, inadequate immune responses). To provide insight into the events that determine how EBV infects epithelial cells and enhance our understanding of the pathogenesis of OHL. Procedures in the Proposal: To test the hypothesis a cell culture system will be established in which direct lytic infection by EBV or efficient induction of lytic infection following latent infection can be demonstrated in epithelial cells. Specific aims are: 1) Analyze an immortalized, non-tumorigenic epithelial cell line that naturally expresses the virus receptor and can be stably infected upon selection with recombinant EBV. Explore how the receptor mediates attachment, internalization and signaling and determine which genes are expressed upon entry. Compare the ability of different virus strains to produce efficient infection and assess whether early infection has a lytic component. Determine whether early lytic replication can be activated by specific cytokines (as might be altered in HIV infection) and will study events that cause switching from the latent program established by recombinant virus selection in vitro to the lytic program that has been observed in vivo (inducers of differentiation, immediate early gene transfer, antagonists of oncogene expression). 2)Apply observations to the establishment of a normal epithelial cell culture system. Obtain normal oral keratinocytes of lateral tongue origin, keratinocytes from this site engineered to express HPV 16 E6 and/or E7 naturally arising preneoplastic and fully malignant from this site. These cells will be examined for receptor expression, infectibility, and for the type of EBV infection they are able to support in two types of conventional culture systems as well as in organotypic culture. The effects of exposure of cells to inflammatory mediators (as might be altered in HIV infection) will be assessed relative to receptor expression and the pattern of virus infection. 3)Study the biology of specific lytic viral genes in the epithelial line and oral keratinocytes in culture. Initial studies will focus on the immediate early transactivators. These genes will be introduced by retrovirus mediated gene transfer under the control of an inducible promotor and their capacity to alter the state of differentiation of the cell in the absence/ presence of EBV infection and together with specific inflammatory mediators will be assessed.