RETROVIRUS REGULATION IN VITRO AND DURING DEVELOPMENT

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A well documented feature of retroviruses is that most virus isolates, although able to replicate in a wide variety of tissues in infected animals, induce tumors in only one or a small number of cell types. For non-acute transforming avian and murine retroviruses, which by definition do not contain viral-associated oncogenes, the specificity of tumor induction as well as the frequency with which a virus causes disease, segregate primarily with the long terminal repeat (LTR) that contains the viral enhancer and promoter. Experiments are proposed in this application to use avian non-acute transforming viruses to investigate properties of different viral LTRs that define (a) the frequency and (b) the specificity of tumor induction and (c) the mechanism(s) employed to disrupt expression of cellular genes at sites of provirus integration in tumors. These areas are investigated by defining the transcriptional properties of wild type, mutant, and recombinant LTRs from highly and weakly oncogenic viruses and by in vivo oncogenicity testing of replication competent viruses that include these LTRs. Experiments are also included to characterize a novel common integration site (bravo) that has been defined in avian retrovirus induced B cell lymphomas and to determine the effects of provirus integration at this locus. Studies in this application will contribute to our understanding of the identity and regulation of viral elements involved in tumor induction and of the role that cellular transcription factors and cellular oncogenes play in this process as well. In addition, the proposed studies on the bravo locus are likely to yield important information in light of the fact that many of the previously characterized common provirus integration sites in tumors identify genes that contribute to both normal cell growth, differentiation or development and, in their abnormal form, to cellular transformation.