Regulation of Human Papillomavirus Gene Expression

DESCRIPTION (provided by applicant): The overall goal of our studies is to understand the mechanisms that regulate viral and cellular gene expression during the productive life cycle of human papillomaviruses (HPVs). Papillomaviruses are small DNA viruses that induce a variety of proliferative epithelial lesions. Over 100 different types of papillomaviruses have been identified and a subset of these including types 16, 18 and 31 are the etiological agents of cervical cancer. The life cycle of papillomaviruses is tightly linked to epithelial differentiation with the induction of late gene expression, genome amplification, and assembly of virions restricted to suprabasal cells. My laboratory first developed methods to grow human papillomaviruses in tissue culture and extended these methods to synthesize HPVs from cloned DNA. These methods have allowed for a detailed genetic analysis of the productive life cycle. During the current funding period, we examined the transcriptional transactivation function of E2 in viral pathogenesis, demonstrated a differentiation-induced change in chromatin configuration around the late promoter, identified major posttranscriptional regulatory elements controlling polyadenylation and characterized alterations in cellular gene expression induced by HPV gene products. In this renewal application, I propose to continue our analyses of HPV transcriptional control by focusing on the following questions: 1). What is the relative contribution of replication and differentiation to activation of the late promoter? 2). How does chromatin remodeling contribute to activation of late gene expression? 3). How does the posttranscriptional control element in L2 influence differentiation-dependent viral gene expression?