Human Papillomavirus Infection and Expression of COX-2

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Background: Human Papillomaviruses (HPVs) cause both benign and malignant epithelial tumors in humans. They also cause latent infections of skin and mucus membranes of the airway and genital tract, with long-term persistence of the virus. Recurrent respiratory papillomatosis (RRP), benign papillomas caused primarily by HPV6 and HPV11, is associated with a high degree of morbidity and significant mortality due to the need for frequent surgical removal. Activation of latent airway HPV infection is believed to be the cause of recurrent disease, however the mechanism of activation is yet unknown. There is currently no therapy that will prevent recurrence. Papilloma cells have multiple alterations in signal transduction pathways associated with the EGF receptor, which result in expression of cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE2). COX-2/PGE2 contributes to the growth and viability of papilloma cells, and increases viral expression. Elevated levels of COX-2 are also seen in genital papillomavirus infections, and early clinical studies have found that inhibition of COX-2 significantly improves both RRP and cervical dysplasia. This study will address the molecular mechanism(s) of the clinical response to COX-2 inhibition by celecoxib, particularly focusing on PGE2. Understanding these mechanisms will shed light on the etiology of disease and will instigate novel therapeutic approaches targeting these mechanisms . We hypothesize that elevated levels of PGE2 play an important role in papillomavirus pathogenesis by activating signal transduction pathways that enhance viral expression and suppress cellular differentiation and apoptosis. The specific aims will test this hypothesis in vitro and in vivo by 1) elucidating the signal transduction pathways activated by PGE2 in papilloma cells, 2) determining the mechanism of PGE2-enhanced HPV6/11 expression, 3) determining the effects of PGE2 on the phenotype of papilloma cells, and 4) determining whether COX-2/PGE2 enhances activation of latent papillomavirus in an animal model.