ART On Oral Tissue Growth, Function, and HPV Infections

描述(由申请人提供)：高效抗逆转录病毒疗法(HAART)的使用使艾滋病毒/艾滋病成为一种可控的情况。口腔表现往往是艾滋病毒感染的最早和最重要的指标。口腔健康与身体和心理健康的改善密切相关，不良的口腔健康可能导致不完全坚持治疗方案，有可能使患者复发，并增加发展抗药性病毒的潜力。HAART的使用显著减少了严重的不良口腔疾病，如口腔毛状白斑、坏死性溃疡性牙周炎和口腔念珠菌病。接受抗逆转录病毒治疗(ART)的患者表现出HPV口腔疣发展的显着增加；特别是在表现为CD4细胞计数增加和HIV载量减少的患者。我们假设ART的使用与HPV口腔病变的增加直接相关。为了了解ART如何影响口腔病变的增加，我们需要填补知识中的几个重要空白。我们的所有研究都将依赖于使用我们的三维器官型木筏培养系统。RAFT培养组织已被证明忠实地模拟了它在体内的对应物，并代表了一种与生理相关的体外模型。我们在使用木筏养殖技术方面有近20年的经验。 具体目的1研究ART对口腔上皮细胞生长、分化和创面愈合的影响。ART对生长、分化和伤口愈合的不利影响将对口腔健康产生负面影响，并为观察到的HPV感染和生物学变化提供机制。扁桃体、口腔和牙龈上皮将被研究。特定目的2建议研究HPV在口腔上皮细胞中的复制。目前，尚不清楚口腔上皮细胞是否允许复制感染性HPV，以及ART对HPV允许复制有什么影响。如果口腔组织有缺陷，不能允许复制，那么AIM 2的设计目的是定义病毒生命周期中缺陷的性质。生产性口腔病变会使口腔成为HPV潜在传播的场所。在目标2中，我们还将研究ART是否能够增加口腔上皮细胞的传染性，为使用HAART的HIV/AIDS患者增加口腔病变提供机制。具体目标3建议定义HPV32和HPV16口腔上皮细胞的分化依赖的生命周期，并测试ART对其生命周期的影响。目前，人们对HPV32的生命周期和口腔上皮组织中HPV16的生命周期知之甚少。我们的研究将提供这两种HPV在口腔上皮细胞中的生命周期以及ART如何影响它们的生命周期的广泛地图。我们假设ART的一些作用将与感染的病理有关，例如HPV癌基因E6和E7表达的增加。

DESCRIPTION (provided by applicant): Use of highly active antiretroviral therapy (HAART) has made HIV/AIDS a manageable condition. Oral manifestations are often the earliest and most important indicator of HIV infections. Oral health is significantly linked to both physical and mental health improvement, and adverse oral health can lead to incomplete adherence to treatment regimens risking relapse in the patient and increasing the potential for development of drug resistance viruses. Use of HAART has resulted in a significant reduction in serious adverse oral conditions such as oral hairy leukoplakia, necrotizing ulcerative periodontitis, and oral candidiasis. Patients taking antiretroviral therapy (ART) have shown a significant increase in the development of HPV oral warts; particularly in patients presenting increased CD4 cell counts and reduced HIV load. We hypothesize that ART use is directly related to the increase of HPV oral lesions. To understand how ART is affecting the increase in oral lesions several important gaps in our knowledge need to be filled in. All of our studies will depend on using our three-dimensional organotypic raft culture system. Raft culture tissue has been to shown faithfully mimic its in vivo counterpart and represents a physiological relevant in vitro model. We have nearly 20 years experience using raft culture technology. Specific Aim 1 proposes to investigate the effect of ART on oral epithelial growth, differentiation, and wound healing. Adverse effects of ART on growth, differentiation, and wound healing would have a negative impact on oral health and provide mechanisms for observed changes in HPV infection and biology. Tonsil, buccal, and gingival epithelium will be studied. Specific Aim 2 proposes to study the replication of HPV in oral epithelium. Presently, it is not known if oral epithelium is permissive for replication of infectious HPV and what effect ART has on HPV permissive replication. If oral tissue is defective for permissive replication then Aim 2 is designed to define the nature of the defect in the viral life cycle. Productive oral lesions would make the oral cavity a site for the potential spread of HPV. In Aim 2 we will also investigate if ART is able to increase the infectivity of oral epithelial cells providing a mechanism for the increase in oral lesions seen in HIV/AIDS patients using HAART. Specific Aim 3 proposes to define the differentiation-dependent life cycle of HPV32 and HPV16 oral epithelium and test the effects of ART on their life cycles. Presently, nothing is known in any system about the life cycle of HPV32 and little is know about the life cycle of HPV16 in oral epithelial tissues. Our studies will provide an extensive map of the life cycles these two HPVs in oral epithelium and how ART impinges on their life cycles. We hypothesize that some of the effects of ART will be related to pathology of the infections, such as increases in HPV oncogenes E6 and E7 expression.