TAP-1/E7 INTERACTION: ROLE IN RESPIRATORY PAPILLOMAS

描述(申请人提供)：喉乳头状瘤病为人类 乳头瘤病毒(HPV)介导的疾病以多次复发和 经常做手术以维持呼吸道通畅。我们发现这些被感染的 细胞将抗原呈递给循环中的CD8 T细胞的能力受损。 TAP-1(与抗原相关的转运蛋白)似乎是 喉乳头状瘤病(HPV6111型)减少。耐人寻味的新结果 这让我们假设这个负责抗原的关键转运体 可能不是缺少演示文稿，而是因为与 E7病毒蛋白、TAP-1不可用。这种交互作用赋予了一个功能 结果：纯化的HPV11E7蛋白抑制了ATP依赖的多肽 体外转运。在HPV11中观察到的TAP-1 E7相互作用似乎发生了 根据初步的免疫沉淀数据，HPV16也是如此， 引出了我们的假设：我们假设其中一个保守的结构域 的E7与TAP-1相互作用并在功能上禁用它。此应用程序具有 检验假说的三个具体目的：1.确定临界区 HPV11E7与TAP-1的物理相互作用所必需的，并分析 这一关键区域也会对转运蛋白产生功能抑制。2. 确定TAP-1或E7的多态是否可以部分解释 疾病易感性的变化。3.确定交互是否 在TAP-1和E7之间的自然发生感染足以导致 多肽转运的损失以及这种损失是否与病毒蛋白相关 负荷与患者的临床病程。

DESCRIPTION (provided by applicant): Laryngeal papillomatosis is a Human Papillomavirus (HPV) mediated disease characterized by multiple recurrences and frequent surgeries to maintain an airway. We have found that these infected cells have an impaired ability to present antigen to circulating CD8 T cells. TAP-1 (the Transporter Associated with Antigen Presentation) appeared to be reduced in laryngeal papillomatosis (HPV type 6111). Intriguing new results have lead us to postulate that this key transporter responsible for antigen presentation may not be lacking, but rather, because of an interaction with the E7 viral protein, TAP-1 is unavailable. This interaction imparts a functional consequence: purified HPV 11 E7 protein inhibited ATP-dependent peptide transport in vitro. The TAP-1 E7 interaction observed in HPV 11 seems to occur with HPV 16 as well, according to preliminary immunoprecipitation data, which has lead us to our hypothesis: we hypothesize that one of the conserved domains of E7 interact with TAP-1 and functionally disables it. This application has three specific aims to test the hypothesis: 1. To determine the critical region of HPV 11 E7 necessary for a physical interaction with TAP-1 and analyze whether this critical region also imparts functional inhibition of the transporter. 2. To determine if polymorphisms of TAP-1 or E7 can partially account for variations in disease susceptibility. 3. To determine whether the interaction between TAP-1 and E7 in naturally occurring infections sufficient to result in a loss of peptide transport and whether this loss correlates with viral protein load and the patients clinical course.