Combined Effect on HIV and HPV in Oral Cancer

描述（由申请方提供）：有新的证据表明人类免疫缺陷病毒（HIV）通过其反式激活因子（达特）蛋白直接致癌。达特靶向哺乳动物基因组的“守门人”，即，p53和RB 2/p130肿瘤抑制因子，并可能通过损害DNA修复活性来挑战遗传稳定性。达特还可介导HIV与其它致癌病毒（如人乳头瘤病毒（HPV））的相互作用。达特从HIV感染的细胞中释放，并能够渗透到靶细胞中，包括那些携带HPV DNA的细胞。在免疫功能低下的儿童和感染艾滋病毒的成人中，经常发现口腔中的HPV感染。HIV+患者更容易感染多种HPV亚型，包括16型和18型。这些“高危”HPV与恶性口腔癌的发生密切相关。然而，单独的HPV感染不足以引起致瘤细胞转化，这需要额外的致癌刺激。重要的是，达特正调控HPV长控制区（LCR），以提高E6和E7病毒癌基因的表达。因此，HIV可能通过达特增强HPV的致瘤潜力。 我们的长期目标是阐明HIV达特在携带“高危”HPV基因组的人口腔角质形成细胞恶性转化中的作用。 该项目的中心假设是HIV达特增强了HOK中HPV的致瘤性。我们将通过以下具体目的来检验这一假设：（1）研究HIV达特对表型改变的影响，即，（2）检测HIV达特对携带HPV基因组的NHOK和HOK永生化和致瘤性的影响;（3）鉴定HIV达特转导在携带HPV基因组的NHOK和HOK中差异表达的细胞基因和蛋白。这些研究将最终引导我们开发一种新的模式，用于HIV+患者中HPV相关口腔病变的早期诊断和治疗。 达特蛋白是人类免疫缺陷病毒（humanimmunodeficiencyvirus，HIV）的基因产物之一，在HIV阳性患者的肿瘤发生中起重要作用。在这项研究中，我们将研究达特蛋白在癌症发展中的作用，特别是在口腔组织中与人乳头瘤病毒（HPV）相关的癌症。

DESCRIPTION (provided by applicant): There is emerging evidence to suggest the direct oncogenic potential of human immunodeficiency virus (HIV) through its trans-activator (Tat) protein. Tat targets the "gate keepers" of mammalian genome, i.e., p53and RB2/p130 tumor suppressors, and may challenge genetic stability by impairing DMA repair activities. Tat may also mediate the interactions of HIV with other oncogenic viruses, such as human papilloma virus (HPV).Tat is released from HIV-infected cells and is capable of penetrating into the target cells, including those harboring HPV DMA. Frequent infection with HPV in the oral cavity has been noted in immunocompromised children and adults infected with HIV. HIV+ patients are more susceptible to infection with multiple HPV subtypes, including types 16 and 18. These "high risk" HPVs are closely associated with development of malignant oral cancer. However, HPV infection alone is not sufficient for tumorigenic cell transformation, which requires additional oncogenic stimuli. Importantly, Tat positively regulates the HPV long control region (LCR) to elevate the expression of E6 and E7 viral oncogenes. Therefore, HIV may enhance the tumorigenic potential of HPV, possibly through Tat. Our long-range goal is to elucidate the role of HIV Tat in the malignant conversion of human oral keratinocytes harboring "high risk" HPV genome. The central hypothesis of this project is that HIV Tat enhances the tumorigenicity of HPV in HOKs. We will test this hypothesis through the following Specific Aims: (1) to investigate the effects of HIV Tat on phenotypic alteration, i.e., proliferation, differentiation, senescence, and apoptosis, of NHOK and HOK harboring HPV genome, (2) to determine the effects of HIV Tat on immortalization and tumorigenic potential of NHOK and HOK harboring HPV genome, (3) to identify the cellular genes and proteins differentially expressed by HIV Tat transduction in NHOK and HOK harboring HPV genome. These studies will ultimately lead us to develop a novel mode for early diagnosis and treatment of HPV-related oral lesions in HIV+ patients. There is emerging evidence to suggest that Tat protein, one of gene products from human immunodeficiency virus (HIV), plays important role in the development of cancer in HIV+ patients. In this study, we will examine the role of Tat protein in the development of cancers, particularly human papilloma virus (HPV)-related cancer in oral tissue.