Effect of ART on 3D Oral Epithelium & KSHV/RRV Infection

描述(申请人提供)：随着高效抗逆转录病毒疗法(HAART)的出现，艾滋病毒/艾滋病已成为一种可控的疾病。口腔表现往往是艾滋病毒感染的最早和最重要的指标。HAART显著减少了一些与艾滋病相关的口腔疾病。然而，口腔卡波西肉瘤(KS)，HIV感染最常见的口腔并发症之一，报告使用HAART后几乎没有变化。目前，抗逆转录病毒治疗(ART)对口腔KS生物学的影响尚不清楚。我们假设可以建立体外三维口腔上皮模型来研究口腔KS的病理学和分子生物学，并探讨ART对口腔KS的影响。利用探索性/发展性R21机制，我们建议建立体外三维口腔上皮细胞模型，用于研究KSHV(KS的病原体)感染和复制。在我们的第一个特定目标中，我们建议使用这个模型来研究ART对口腔上皮细胞中KSHV生命周期的影响。将使用三种不同的口腔模型，包括扁桃体、口腔和牙龈上皮。这些模型将支持对控制表达谱的病毒-宿主相互作用机制的研究，以及重要的是特定的ART或ART类别如何影响KSHV生命周期的分子生物学。它们还将提供一个平台，在这个平台上可以测试新的抗逆转录病毒疗法的副作用。 灵长类动物模型是研究艾滋病和艾滋病相关感染的优秀模型，但使用灵长类动物的成本很低。我们假设，器官类型的灵长类口腔上皮移植物培养可以提供一个相对简单和廉价的系统，使用与生理相关的组织模型来补充和集中灵长类研究。在我们的第二个具体目标中，我们建议建立三维灵长类口腔上皮模型，以研究ART对其生长和分化的影响。RhadinVirus(RRV)是KSHV的灵长类同源物。类似于人类组织中的KSHV，我们将研究ART对口腔灵长类动物上皮中RRV感染和复制的影响。我们的灵长类动物体外组织模型将成为研究HIV相关口腔疾病和ART对口腔的影响的重要新工具。 由于口腔KS在艾滋病毒/艾滋病人群中仍然是一个临床上重要的问题，并影响生活质量，因此持续需要使用抗逆转录病毒疗法来管理艾滋病毒感染人群。随着越来越多的患者服用ART的时间更长，了解KS的ART效果变得越来越重要。我们在这一应用方面的研究以及由此发展而来的未来研究将对医疗保健产生重大影响。

DESCRIPTION (provided by applicant): With the advent of highly active antiretroviral therapy (HAART) HIV/AIDS has become a manageable condition. Oral manifestations are often the earliest and most important indicator of HIV infections. HAART has significantly reduced some AIDS-related oral maladies. However, oral Kaposi's sarcoma (KS), one of the commonest oral complications of HIV infection, has reported little change with HAART use. Presently, nothing is known of the effect of antiretroviral therapy (ART) on the biology of oral KS. We hypothesize that in vitro three-dimensional oral epithelial models can be developed to study oral KS pathology, molecular biology, and investigate the effects of ART on oral KS. Using the exploratory/development R21 mechanism we are proposing to develop in vitro three-dimensional oral epithelial models for the study of KSHV (the etiological agent of KS) infection and replication. In our first specific aim we propose to use this model to investigate the effect of ART on the life cycle of KSHV in oral epithelium. Three different oral models will be used consisting of tonsil, buccal, and gingival epithelium. These models will support investigations on the mechanisms of the virus-host interactions that control the expression profiles and importantly how a specific ART or a category of ART is impinging on the molecular biology of the KSHV life cycle. They will also provide a platform on which new antiretroviral therapies can be tested for adverse effects. Primate models are excellent models for the study of AIDS and AIDS-associated infections, however the cost of using primates is inhibiting. We hypothesize that organotypic raft cultures of primate oral epithelium can provide a relatively simple and less expensive system using a physiologically relevant tissue model to complement and focus primate studies. In our second specific aim we propose to develop three-dimensional primate oral epithelial models to study the effect of ART on their growth and differentiation. Rhadinovirus (RRV) is the primate homolog of KSHV. Similar to KSHV in human tissues we will investigate the effect of ART on RRV infection and replication in oral primate epithelium. Our in vitro primate tissue models will be important new tools for the study of HIV-associated oral diseases and ART induced effects on the oral cavity. Because oral KS in the HIV/AIDS population is still a clinically important problem and effects quality of life there is a continuous need to use antiretroviral therapies to manage the HIV infected population. As more and more patients take ART for longer period of times understanding the effect of ART of KS increases in importance. Our studies in this application and future studies evolving from them will have a significant impact on health care.