The broad aim of this research is to continue our multidisciplinary studies on the natural history of bovine leukemia, and important and, in some respects, unique model system for studies of viral leukemogenesis in an outbred animal species. A major objective of the proposed research is to examine the molecular mechanism of BLV-induced leukemogenesis. Using recombinant DNA technique, we propose to study the importance of insertional location of BLV proviral DNA and the expression of both, BLV provirus itself and adjacent cellular sequences, in the development of bovine lymphosarcoma. Another objective is to examine the factors responsible for the repressed state in which BLV is usually present in its natural target cell. This objective includes on the nature and mechanism of action of a non-immunoglobulin plasma factor that blocks the expression of BLV. Our proposal includes the study of the natural mode of transmission of BLV, and of the possibility that the virus may infect other animal species. We also propose to examine the virus-host and tumor-host immunological interaction in cattle with high and low risk of leukemia. Central to our program is maintenance of the multiple-case study herd BF, in a highly defined state. This herd provides an unparalleled source of animals with high and low leukemia risk and of essential biological materials.