Life Cycle of Human Papillomaviruses

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to investigate the mechanisms, which regulate the productive life cycle of human papillomaviruses (HPV). Papillomaviruses are small DNA viruses that induce a variety of proliferative lesions in most mammals including humans. Of the 100 types of human papillomaviruses that have been identified, a subset are associated at a high frequency with anogenital cancers and these are referred to as the high risk types (16, 18, 31, 33 and 51). Viral infection occurs into stratified epithelial cells and results in an altered pattern of differentiation from that seen in normal cells. The production of viral particles, genome amplification, capsid protein synthesis, and virion assembly is dependent upon differentiation and is restricted to suprabasal cells. In 1996, my laboratory developed methods to synthesize HPV 31 virions from cloned transfected DNA templates following differentiation in organotypic cultures. In this renewal application, I propose to continue these studies by examining the roles of E6 and E5 in the productive life cycle. Recent studies from my laboratory as well as those of other laboratories identified important roles for E6 in plasmid maintenance and E5 for differentiation-dependent viral functions. In this renewal application, I propose to utilize the genetic system my laboratory has developed to examine these activities in the context of the complete HPV genome during the differentiation-dependent viral life cycle. I will ask the following questions: 1). What is the role of E6 in plasmid maintenance? a). Can insights be provided through a mutational analysis of low and high risk E6 proteins? b). Is the p53 pathway altered in BPV 11 positive cells and is it a target of E6 action? c). Which binding partners of low and high risk E6 proteins are necessary for episomal maintenance? 2). What is the role of E5 during the productive phase of the viral life cycle? a). What are the characteristics of differentiating keratinocytes that contain E5 mutant HPV 31genomes? b). Which mutations of E5 abrogate the ability to efficiently activate late functions? c). Where is the E5 protein localized in differentiating epithelia? d). Are 16kD protein or EGF receptors of HPV 31 E5 action? e). Are there other cellular targets of E5 action?
StatusFinished
Effective start/end date8/6/037/31/07

Funding

  • National Cancer Institute (3 R01 CA074202-07S1)

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