TAP-1/E7 INTERACTION: ROLE IN RESPIRATORY PAPILLOMAS

描述（由申请人提供）：喉乳头状瘤病是一种人类 乳头瘤病毒（HPV）介导的疾病，其特征在于多次复发， 经常做手术来维持呼吸道我们发现这些感染者 细胞将抗原呈递给循环CD 8 T细胞的能力受损。 TAP-1（与抗原呈递相关的转运蛋白）似乎是 喉乳头状瘤病（HPV 6111型）减少。有趣的新结果 这让我们假设这个负责抗原的关键转运蛋白 可能并不缺乏介绍，而是因为与 E7病毒蛋白，TAP-1不可用。这种相互作用赋予了功能性的 结果：纯化的HPV 11 E7蛋白抑制ATP依赖性肽 体外运输在HPV 11中观察到的TAP-1 E7相互作用似乎发生在 根据初步的免疫沉淀数据， 这让我们提出了假设：我们假设其中一个保守的结构域 的E7与TAP-1交互并在功能上禁用它。该应用程序具有 三个具体的目的来检验假设：1。为了确定临界区域 与TAP-1发生物理相互作用所必需的HPV 11 E7，并分析 该关键区域还赋予转运蛋白功能性抑制。2. 为了确定TAP-1或E7多态性是否可以部分解释 疾病易感性的变化。3.为了确定是否相互作用 TAP-1和E7在自然发生的感染中的差异足以导致 肽转运的损失以及这种损失是否与病毒蛋白相关 负荷和患者的临床病程。

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.