The structural, functional and biological similarities of bovine leukemia virus (BLV) to human T cell leukemia viruses (HTLV) make BLV in cattle an excellent model to study oncogenic retroviral infections in humans. The long term objectives of this proposal are to define the relationship between the regulation of BLV transcriptional activation, and the activation and proliferation of B lymphocytes, the primary host cell target of BLV.
The specific aims designed to accomplish these objectives in Phase I of the SERCA proposal are: 1. Characterize the interactions between BLV and cellular nuclear binding proteins and map the DNA-protein binding sites in the BLV provirus. The binding of putative nuclear transcription factors to the BLV LTR will be mapped using DNase I footprinting. 2. Identify and characterize transcriptional factors specifically associated with B cell activation that bind to the BLV promoter. Transcriptional factors from resting and activated bovine lymphocytes will be identified, and analyzed using the BLV LTR map. 3. Determine the role of the intracellular second messengers PKC and PKA in induction of BLV transcription. PKC and PKA inhibitors and activators will be used to define the roles of cellular PKC and PKA in BLV transcriptional activation. The last specific aim will be accomplished during Phase II of the SERCA proposal: 4. Determine the effects of BLV Tax on the nuclear binding protein's that interact with the BLV promoter. A Tax fusion protein will be developed to study Tax effects on BLV and B cell activation. These studies will provide new insights into the pathogenesis of oncogenic retroviruses, and will provide an excellent framework for training the candidate in molecular biological research.
