Combined Effect on HIV and HPV in Oral Cancer

描述(由申请人提供)：有新的证据表明，人类免疫缺陷病毒(HIV)通过其反式激活蛋白(TAT)具有直接致癌潜力。TAT针对哺乳动物基因组的“守门人”，即p53和rb2/p130肿瘤抑制因子，并可能通过损害DMA修复活动来挑战遗传稳定性。Tat还可能介导HIV与其他致癌病毒的相互作用，如人乳头瘤病毒(HPV)。Tat从感染HIV的细胞中释放出来，并能够穿透到靶细胞，包括那些携带HPV DMA的细胞。在感染艾滋病毒的免疫功能低下的儿童和成人中，已注意到口腔中频繁感染HPV。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与恶性口腔癌的发展密切相关。然而，仅有HPV感染是不足以使致瘤细胞转化的，这需要额外的致癌刺激。重要的是，TAT正向调节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。 我们的长期目标是阐明HIV TAT在携带高危HPV基因组的人类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 TAT增强了HOK中HPV的致瘤性。我们将通过以下特定目的来验证这一假说：(1)研究HIV Tat对携带HPV基因组的NHOK和HOK的表型变化(即增殖、分化、衰老和凋亡)的影响；(2)确定HIV Tat对携带HPV基因组的NHOK和HOK永生化和致瘤潜能的影响；(3)鉴定转导HIV Tat在携带HPV基因组的NHOK和HOK中差异表达的细胞基因和蛋白质。这些研究最终将引导我们开发一种新的模式，用于HIV患者HPV相关口腔病变的早期诊断和治疗。 越来越多的证据表明，Tat蛋白是人类免疫缺陷病毒(HIV)的基因产物之一，在HIV患者的癌症发生发展中发挥着重要作用。在这项研究中，我们将研究TAT蛋白在癌症发展中的作用，特别是口腔组织中人类乳头瘤病毒(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.