PATHOGENESIS OF ORAL HAIRY LEUKOPLAKIA

描述：口腔毛状白斑的发展是EB病毒的结果 在HIV感染期间口腔上皮细胞的感染。 特异性辅因子 增强口腔上皮细胞对感染的易感性（不足 或不适当的免疫应答）和/或延长病毒感染者的存活 细胞（与转化病毒共同感染、免疫反应不足）。 为了深入了解决定EBV如何感染上皮细胞的事件， 细胞和增强我们对OHL发病机制的理解。 方案中的程序：检验细胞培养系统的假设 将建立EBV的直接溶解性感染或有效的 可以证明在潜伏感染之后诱导溶解性感染 在上皮细胞中。 具体目标是：1）分析永生化的非致瘤性上皮细胞， 天然表达病毒受体并可稳定表达的细胞系 在用重组EBV选择后感染。 探索受体如何 介导附着、内化和信号传导，并决定哪些基因 在入境时表示。 比较不同病毒株的能力， 产生有效的感染，并评估早期感染是否具有溶解性 成分 确定早期裂解性复制是否可以通过 特异性细胞因子（如可能在HIV感染中改变），并将研究 导致从由以下步骤建立的潜在程序切换的事件 重组病毒的体外选择裂解程序，已 在体内观察到（分化诱导剂，立即早期基因 转移，癌基因表达的拮抗剂）。 2)将观察结果应用于建立正常上皮细胞 培养体系 获取正常舌侧来源的口腔角质形成细胞， 来自该位点的角质形成细胞被工程化以表达HPV 16 E6和/或E7 从该部位自然产生的癌前病变和完全恶性病变。 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， 培养系统以及器官型培养。 曝光的效果 细胞的炎症介质（可能会改变艾滋病毒感染） 将相对于受体表达和病毒模式进行评估 感染 3)研究上皮细胞系中特异性裂解病毒基因的生物学， 口腔角化细胞培养。 初步研究将侧重于 早期反式激活因子 这些基因将通过逆转录病毒导入 在诱导型启动子控制下的介导的基因转移， 在不存在/不存在细胞的情况下改变细胞分化状态的能力。 存在EBV感染，并与特定炎症介质一起 将被评估。

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.