ART Modulation of Viral Pathogenesis in Oral Epithelia

描述（由申请人提供）：本R 01申请是对RFA-DE-07-002的回应，旨在研究抗逆转录病毒治疗（ART）对口腔粘膜的长期使用。具体而言，我们将研究口咽组织的变化如何有助于人类疱疹病毒HSV-1，EBV和KSHV的发病机制。这些人类病原体引起不同的疾病表型，从组织破坏性病毒血症（HSV-1）到口腔癌（KSHV，EBV）。不管最终的病理学如何，从病毒潜伏状态的再活化似乎先于疾病，并且在EBV和KSHV的情况下，许多疾病表型是由仅在病毒再活化期间表达的基因产物引起的。我们假设：（a）口腔粘膜上皮表面的变化引起病毒再活化，（B）ART调节生理触发因子和病毒基因谱，导致ART相关病毒性疾病，如口腔KS，这在HIV阴性、ART阴性的所谓经典KS患者或EBV阳性的下颌浆母细胞淋巴瘤中很难见到。 此外，我们将探索ART药物对先天免疫反应的影响，即TLR信号传导，通过使用我们最近开发的NF-κ B实时QPCR阵列来比较颊和牙龈上皮的临床样品和实验模型。

DESCRIPTION (provided by applicant): This R01 application is in response to RFA-DE-07-002 to study the long-term use of antiretroviral therapy (ART) on the oral mucosa. Specifically, we will investigate how changes in the oropharyngeal tissues contribute to the pathogenesis of the human herpes viruses HSV-1, EBV and KSHV. These human pathogens cause different disease phenotype ranging from tissue destructive viremia (HSV-1) to oral cancer (KSHV, EBV). Regardless though of the final pathology, reactivation from a viral latent state seems to precede disease, and in case of EBV and KSHV many of the disease phenotypes are caused by gene products that are only expressed during viral reactivation. We hypothesize that (a) changes in the oral mucosal epithelial surfaces cause virus reactivation and (b) that ART modulates both the physiological trigger and the viral gene profile leading to ART-associated viral diseases such as oral KS, which is hardly seen in HIV-negative, ART-negative so called classic KS patients or EBV-positive plasmablastic lymphomas of the lower jaw. Furthermore, we will explore the effect of ART drugs on the innate immune response, i.e. TLR signaling by using our recently developed NF-kappaB real-time QPCR array to compare both clinical samples and experimental models of buccal and gingival epithelium.