ART On Oral Tissue Growth, Function, and HPV Infections

描述（由申请人提供）：使用高效抗逆转录病毒疗法（HAART）已使艾滋病毒/艾滋病成为一种可管理的疾病。口腔表现往往是艾滋病毒感染的最早和最重要的指标。口腔健康与身心健康的改善密切相关，不良的口腔健康可能导致患者不完全遵守治疗方案，有复发的风险，并增加耐药性病毒发展的可能性。HAART的使用已导致严重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的显著减少。接受抗逆转录病毒治疗（ART）的患者显示HPV口腔疣的发展显着增加;特别是在CD 4细胞计数增加和HIV载量减少的患者中。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。我们所有的研究将依赖于使用我们的三维器官型筏培养系统。筏培养组织已被证明忠实地模仿其在体内的对应物，并代表了生理相关的体外模型。我们有近20年的经验，使用筏式养殖技术。 具体目标1提出研究ART对口腔上皮生长、分化和伤口愈合的影响。ART对生长、分化和伤口愈合的不良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。将研究扁桃体、颊和牙龈上皮。具体目标2提出研究HPV在口腔上皮中的复制。目前，尚不清楚口腔上皮是否允许感染性HPV复制以及ART对HPV允许复制的影响。如果口腔组织对于允许复制是有缺陷的，那么目标2被设计为定义病毒生命周期中缺陷的性质。生产性口腔病变将使口腔成为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感染性，为使用HAART的HIV/AIDS患者中观察到的口腔病变增加提供机制。具体目标3提出定义HPV 32和HPV 16口腔上皮的分化依赖性生命周期，并测试ART对其生命周期的影响。目前，在任何系统中对HPV 32的生命周期都一无所知，对口腔上皮组织中HPV 16的生命周期也知之甚少。我们的研究将提供这两种HPV在口腔上皮中的生命周期以及ART如何影响其生命周期的广泛地图。我们假设ART的某些作用与感染的病理学有关，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.