The broad of this research are to gain now insights into the phenomena of papillomavirus-induced cell transformation, and ultimately malignant conversion, by focusing on the changes in host-cell gene expression and other influences on cell gene products that are linked to the expression of papillomavirus (PV) genes. This work began with a comprehensive examination of changes in about 5000 host-cell gene products in which we described those changes that occurred in cells transformed by the bovine papillomavirus type 1 (BPV-1), by the cottontail rabbit papillomavirus (CRPV) and their cloned PV DNAs, including the responses to a number constructs engineered to alter the expression of early PV ORFs. In this proposal we are proceeding beyond the initial descriptive stage with the immediate aim of gathering more fundamental information about the nature and origins of six seemingly new peptides that appear to represent PV-specific inductions in cellular proteins that appear in BPV-1 and CRPV transformed cells. We will also be exploring a new hypothesis that evolved from our initial studies, namely, that the products of the viral E2 coding region (E2 ORF), which are known to serve as transactivators in the expression of the early viral genes, may also serve as transactivators altering the expression of cellular genes. The research will involve the use of E2 expression vectors to further establish the role of E2 gene products in the origins of the PV-specific changes in cellular proteins. It will examine the products of in vitro translation of recovered cellular mRNAs to determine whether the inductions occur at the level. It will utilize specific antibodies to detect changes in E2 proteins and develop and utilize coding-region specific hybridization probes to detect expression of E2 mRNAs. And it will undertake the molecular cloning of cDNAs to the PV-specific cellular proteins. Potential clinical relevance includes the eventual development of immunoreagents for diagnostic and therapeutic use, and the development of new therapies that enhance cellular resistance to viruses by altering cellular factors or other components involved in transactivating mechanisms that play critical roles in virus- host relationships.
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