AIDS-associated viral infections in human oral tissues

描述(申请人提供)：口腔感染是人类免疫缺陷病毒(HIV)和人类巨细胞病毒(HCMV)传播的重要途径，导致全球后果。人巨细胞病毒感染是引起艾滋病患者口腔疾病的最常见原因之一。此外，在口腔组织中发现了HIV和HCMV，它们之间的相互作用被认为对它们的成功口腔传播以及病毒诱导的口腔疾病的发展起到了重要作用。然而，目前对HCMV和HIV口腔感染的机制知之甚少，部分原因是这些感染主要局限于人类细胞，很少有研究口腔粘膜中HCMV和HTV感染的培养组织或动物模型的报道。最近的体外研究表明，生产性HIV感染发生在正常口腔角质形成细胞中，并在口腔粘膜中存在上调CXCR4受体表达的环境因素(如酒精)时增强。我们的初步研究表明，HCMV能够有效地感染培养的人牙龈和口腔组织，并显著增强培养的口腔黏膜中的HIV感染。本研究的总体目标是建立人牙龈颊组织培养模型，并利用这些培养组织研究人巨细胞病毒和人类免疫缺陷病毒在口腔粘膜中的感染及其相互作用。 在拟议的研究的初始部分，将建立体外人类口腔和牙龈组织培养模型。然后，组织将被一个缺失单个病毒开放阅读框架的巨细胞病毒突变体库感染。在培养组织中生长有缺陷的病毒突变体将被识别和表征。此外，还将研究与病毒口腔感染有关的巨细胞病毒决定簇的功能。最后，在没有和存在不同的HCMV突变体的情况下，组织将被感染HIV，并将探讨HIV口腔感染如何受到HCMV影响的机制。这项研究将导致新的组织培养模型的发展，以研究HIV和HCMV在口腔粘膜中的感染。这些研究还将确定HCMV在口腔粘膜中复制所需的病毒基因，并探讨HIV-HCMV在口腔中相互作用的机制。这一结果将为深入了解HCMV和HIV在口腔粘膜中的感染机制提供依据，并有助于开发新的治疗和预防这些病毒在口腔中的传播和感染的策略。

DESCRIPTION (provided by applicant): Oral infection represents an important route of human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) transmission, leading to global consequences. HCMV infection is among the most common causes of oral diseases associated with AIDS patients. Furthermore, HIV and HCMV are found in oral tissues and their interaction is believed to play an important role for their successful oral transmission as well as for the development of viral-induced oral diseases. However, little is currently known about the mechanism of HCMV and HIV oral infections, partially because these infections are primarily limited to human cells, and few cultured tissue or animal models for studying HCMV and HTV infections in oral mucosa have been reported. Recent in vitro studies indicate that productive HIV infection occurs in normal human oral keratinocytes and is enhanced in the presence of environmental factors in oral mucosa, such as alcohol, which up-regulates CXCR4 receptor expression. Our preliminary studies suggest that HCMV productively infects cultured human gingival and buccal tissues and significantly enhances HIV infection in cultured oral mucosa. The overall objective of this proposed research is to develop human gingival and buccal tissue culture model and use these cultured tissues to study the infection of HCMV and HIV and their interactions in oral mucosa. In the initial part of the proposed study, in vitro human buccal and gingival tissue culture models will be developed. Tissues will then be infected with a library of HCMV mutants with deletion of a single viral open reading frame. Viral mutants that are defective in growth in cultured tissues will be identified and characterized. Furthermore, the function of HCMV determinants essential for viral oral infection will be studied. Finally, tissues will be infected with HIV in the absence and presence of different HCMV mutants, and the mechanism of how HIV oral infection is affected by HCMV will be investigated. The proposed research will lead to the development of new tissue culture models to study HIV and HCMV infection in oral mucosa. These studies will also identify viral genes required for HCMV replication in oral mucosa and investigate the mechanism of HIV-HCMV interactions in oral cavity. The results will provide insight into the mechanism of HCMV and HIV infection in oral mucosa and facilitate the development of novel strategies for treatment and prevention of the transmission as well as infections of these viruses in oral cavity.