AIDS-associated viral infections in human oral tissues

描述（由申请人提供）：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。HCMV感染是与艾滋病患者相关的口腔疾病的最常见原因之一。此外，HIV和HCMV在口腔组织中被发现，它们的相互作用被认为在它们成功的口腔传播以及病毒诱导的口腔疾病的发展中起着重要作用。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，并且很少有研究口腔黏膜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，正常的人口腔角质形成细胞中也会发生生产性HIV感染，并且在口腔黏膜中存在环境因素（如酒精）时，这种感染会增强，从而上调CXCR4受体的表达。我们的初步研究表明，HCMV可有效感染培养的人牙龈和口腔组织，并显著增强培养口腔黏膜的HIV感染。本研究的总体目标是建立人类牙龈和口腔组织培养模型，并利用这些培养组织研究HCMV和HIV在口腔黏膜的感染及其相互作用。

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.