The central theme of the present proposal continues to be the understanding of retroviral insertional mutagenesis and oncogene activation. Avian B-lymphomas are frequently associated with infections by nonacute retroviruses, ALV (avian leukosis virus) and REV (reticuloendotheliosis virus). Avian T-lymphomas are caused primarily by MDV, Marek's disease herpesvirus, but also by REV. These systems have provided excellent models to study retroviral insertional mutagenesis, oncogene identification, cancer vaccine development and interactions between retroviruses and herpesviruses. The PI and the co-PIs have been studying the molecular genetics and oncogenesis of avian retroviruses and herpesviruses. In the past grant period, their joint efforts have resulted in the following interesting findings: (1) retrovirus can efficiently integrate into herpesvirus genome. Evidence was provided to suggest that this can take place in vitro and in vivo. Herpesvirus genes are activated by retroviral insertion and MDV harboring REV LTR has an enhanced growth rate. (2) retrovirus, as exemplified by REV, has an """"""""RNA enhancer"""""""" like element in its leader sequence. This element modulates the activity of 5' and 3' LTR, and influences the mode of protooncogene activation in lymphoma. If established, this would be the first RNA enhancer identified in type-C retroviruses. (3) MDV contains a latent gene, meq, which has the hallmarks of a nuclear oncogene. This gene is present only in the oncogenic strain of MDV and is one of the few genes highly expressed in lymphomas. meq may play an important role in the latency or oncogenesis of MDV. Guided by these interesting leads, we propose to continue these lines of research. More specifically, we wish to further define the nature of the REV RNA enhancer, the structure and function of the putative MDV oncogene meq, and the genetic interaction between REV and MDV in lymphoma. The results from these studies should have implications beyond the avian system and provide fundamental knowledge about retroviral replication, oncogenesis as well as cell regulation.
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