ART On Oral Tissue Growth, Function, and HPV Infections

描述（由申请方提供）：母体R 01的目的是研究抗逆转录病毒治疗（ART）对不同类型口腔上皮中口腔HPV感染生命周期的影响。我们的假设是ART影响宿主组织和/或HPV的自然史，增加HPV感染口腔上皮组织并诱导病理的能力。我们推测ART药物以导致不良口腔健康的方式影响口腔组织。我们假设的基本原理是基于HIV患者在开始高效抗逆转录病毒治疗（HAART）后口腔HPV病变的频率增加，并且所涉及的HPV基因型通常与相同的解剖区域无关。目标和基本原理没有改变。到目前为止，我们积累的数据加强了我们的假设和追求母公司申请目标的理由。母申请有三个目的：（1）确定抗逆转录病毒（ART）药物对三维口腔上皮组织的影响;（2）ART对口腔上皮中HPV允许复制和感染的影响;（3）研究ART治疗背景下口腔上皮中完整的HPV生命周期。对于此竞争性修订应用程序，我们决定专注于实验设计，该设计将提供无偏见的分析，并在分配的时间资源内最大限度地扩展父提案的范围。NICDR/NIH认识到，关于ART对口腔粘膜的影响以及ART对口腔组织HPV感染的影响知之甚少。我们已经完成的研究表明，ART药物可以对牙龈和扁桃体上皮组织的生长和分化表型有显着的影响。我们现在希望通过进行微阵列分析将这些研究提升到一个新的水平，以确定ART药物治疗口腔组织引起的基因表达的整体变化。我们希望微阵列分析提供一个无偏见的测量扁桃体和上皮组织的基因表达的变化，常用的ART药物的影响。我们期望这将揭示与生物学功能相关的途径和基因组，例如细胞生长、致癌作用、伤口愈合和分化，仅举几例，这些生物学功能与我们观察到的表型变化和在患者中观察到的不良副作用相关。我们还成功地开发了持续感染HPV的扁桃体和牙龈细胞系。我们正在提出微阵列研究来测量HPV 16和HPV 32对口腔组织的广泛影响，并提供数据，使我们能够比较和对比不同病毒对不同组织的影响。这将使我们能够比较HPV 16感染口腔和宫颈组织诱导的差异和相似之处，从而深入了解病毒特异性和组织特异性的肿瘤发生机制。此时对微阵列技术的投资将提供符合母提案范围的文字和精神的无偏见分析，从而显著扩大提案的范围。 公共卫生相关性：我们的假设，即ART药物影响口腔组织的方式，导致不利的口腔健康已经加强了收集到这一点的数据。我们建议进行微阵列研究，以衡量HPV 16和HPV 32对口腔组织的广泛影响。这将提供公正的分析，大大扩大提案的范围。

DESCRIPTION (provided by applicant): The goal for the parent R01 was to investigate the effect of antiretroviral therapy (ART) on the life cycle of oral HPV infections in different types oral epithelium. Our hypothesis was that ART affects the host tissue and/or the natural history of HPV, increasing HPV's ability to infect and induce pathology in oral epithelial tissue. We speculated that ART drugs affect oral tissue in a manner that leads to adverse oral health. The rationale for our hypothesis was based on the increased frequency of oral HPV lesions in HIV patients after they begin highly active antiretroviral therapy (HAART) and that the HPV genotypes involved are not normally associated with the same anatomical areas. The goals and rationale have not changed. The data we have accumulated to this point has strengthened our hypothesis and rationale for pursuing the aims of the parent application. The parent application had three aims (1) Determine the effects of anti-retroviral (ART) drugs on three-dimensional oral epithelial tissues; (2) The effect of ART on HPV permissive replication and infection in oral epithelium; and (3) Study the complete HPV life cycle in oral epithelium in the context of ART treatment. For this Competitive Revision application we decided to focus on an experimental design that will provide an unbiased analysis with the greatest ability to expand the scope of the parent proposal within the time resources allotted. The NICDR/NIH recognized that very little is known concerning the effects of ART on oral mucosa and by extension the effects of ART on HPV infection of oral tissues. We have completed studies demonstrating that the ART drugs can have dramatic effect on the growth and differentiation phenotype of gingival and tonsil epithelial tissues. We now want to take these studies to the next level by performing microarray analyses to identify the global changes in gene expression induced by treating oral tissues with the ART drugs. We expect the microarray analyses to provide an unbiased measurement of changes of gene expression in tonsil and epithelial tissues, affected by commonly used ART drugs. We expect that this will reveal pathways and gene sets relating to biological functions such as cell growth, carcinogenesis, wound healing, and differentiation to name a few that would relate to the changes in phenotype we have observed and to the adverse side effects observed in patients. We have also been successful in developing continuously infected HPV tonsil and gingival cell lines. We are proposing microarray studies to measure the wide spread impact that HPV16 and HPV32 have on oral tissue and provide data that will allow us to compare and contrast the impact of different viruses on different tissues. This will allow us to compare the differences and similarities induced by HPV16 infection of oral and cervical tissues providing insights into virus-specific and tissue-specific mechanisms tumorigenesis. Investment at this time in microarray technology will provide unbiased analyses in line with the letter and spirit of the scope of the parent proposal, providing a significant expansion of the proposal's scope. PUBLIC HEALTH RELEVANCE: Our hypothesis that ART drugs affect oral tissue in a manner that leads to adverse oral health has been strengthened by data collected to this point. We propose to conduct microarray studies to measure the wide spread impact that HPV16 and HPV32 have on oral tissue. This will provide unbiased analyses, providing a significant expansion of the proposal's scope.