The role of the Marek's disease virus (MDV) Meq oncoprotein in the pathogenesis of Marek's disease and the development of MDV vaccine strains

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Recently, a binding motif (20PLDLS24) was identified for the cell co-repressor CtBP in the Meq nuclear oncoprotein encoded by MDV. This is similar to binding sites in oncoproteins EBNA3A and EBNA3C of Epstein-Barr virus (EBV). MDV is a lymphotropic alphaherpesvirus of chickens which, like EBV, can induce malignant disease. The T cell hyperplasia it produces is responsible for many of the symptoms of Marek's disease (MD). By constructing mutants of Meq in a bacterial artificial chromosome (BAC) clone of MDV, it was shown that this interaction between Meq and CtBP is essential for oncogenicity in chickens. This genetically engineered, attenuated strain of MDV very effectively protects chicks from further challenge with very virulent strains of MDV and has potential as a vaccine. In order to determine the role of the leucine zipper in Meq and of Meq dimerisation in lymphomagenesis, specific point mutations were engineered into the highly oncogenic RB-1B-BAC to produce virus completely lacking a functional Meq leucine zipper and virus encoding Meq that cannot homodimerize, but can still bind to c-Jun. Both of these mutant viruses are non-oncogenic. We conclude that the leucine zipper is necessary for the oncogenic activity of Meq and/or the establishment of long-term MDV latency in T cells. Moreover, it appears that the ability to form repressive homodimeric Meq complexes is an absolute requirement for the cancer associated with virulent MDV. We will determine the roles of Meq in non-malignant, but rapidly fatal CNS-associated MD. We will identify specific target chicken genes that are regulated by Meq and establish the roles of interacting protein partners of Meq. It should also be possible to establish what role Meq plays in viral latency and replication in vivo and explore the molecular characteristics of MDV that constitute an effective vaccine for the prevention of MD.

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