Combined Effect on HIV and HPV in Oral Cancer

描述（由申请人提供）：越来越多的证据表明，人类免疫缺陷病毒（HIV）通过其反式激活物（Tat）蛋白具有直接致癌的潜力。它靶向哺乳动物基因组的“看门人”，即p53和RB2/p130肿瘤抑制因子，并可能通过损害DMA修复活性来挑战遗传稳定性。它也可能介导HIV与其他致癌病毒（如人乳头瘤病毒（HPV））的相互作用。它从hiv感染的细胞中释放出来，能够穿透目标细胞，包括那些携带HPV DMA的细胞。在免疫功能低下的儿童和感染艾滋病毒的成人中，口腔中经常感染HPV。HIV阳性患者更容易感染多种HPV亚型，包括16型和18型。这些“高风险”hpv与恶性口腔癌的发展密切相关。然而，HPV感染本身并不足以致瘤细胞转化，这需要额外的致瘤刺激。重要的是，Tat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Tat增强HPV的致瘤潜能。

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.