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.