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

描述（由申请人提供）：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制的疾病。口腔表现往往是艾滋病毒感染的最早和最重要的指标。HAART疗法显著减少了一些与艾滋病有关的口腔疾病。然而，口服卡波西肉瘤（KS）是HIV感染最常见的口腔并发症之一，据报道，使用HAART后几乎没有变化。目前，抗逆转录病毒治疗（ART）对口服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病理、分子生物学以及ART对口腔KS的影响。利用R21的探索性/发展性机制，我们建议开发体外三维口腔上皮模型，用于研究KSHV （KS的病原）的感染和复制。在我们的第一个具体目标中，我们建议使用该模型来研究ART对口腔上皮中KSHV生命周期的影响。三种不同的口腔模型将被使用，包括扁桃体、颊上皮和牙龈上皮。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，重要的是，一种特定的抗逆转录病毒药物或一类抗逆转录病毒药物如何影响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。

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.