Marek's Disease Virus (MDV) Meq Oncoprotein Plays Distinct Roles in Tumor Incidence, Distribution, and Size

Marek's disease (MD), characterized by the rapid onset of T-cell lymphomas in chickens, is caused by Mardivirus gallidalpha2, an oncogenic alphaherpesvirus commonly known as Marek's disease virus (MDV). MDV encodes a bZIP protein, Meq, which contains a bZIP domain (basic DNA-binding and leucine zipper dimerization domain) at the amino terminus and a transcriptional regulatory domain at the carboxyl end. Meq can transform murine and chicken fibroblasts in vitro and is essential for tumor formation in chickens. Meq homodimerization and heterodimerization through its bZIP domain are involved in Meq-mediated transformation. However, the role of Meq DNA-binding and transcriptional regulatory domains in transformation has not been investigated. In this study, we constructed recombinant Md5 (very virulent MDV) viruses expressing chimeric Meq proteins generated by swapping the DNA-binding and transcriptional regulatory domains of Meq of Md5 and vaccine (CVI988/Rispens) strains. Our results show that these recombinant viruses, rMd5-Md5/CVI-Meq (Md5 DNA-binding domain and CVI transcriptional regulatory domain) and rMd5-CVI/Md5-Meq (CVI DNA-binding domain and Md5 transcriptional regulatory domain), replicated at levels similar to parental rMd5 in cell culture and chickens and could transmit efficiently among chickens. Interestingly, parental rMd5 and chimeric viruses exhibited distinct pathogenic phenotypes in chickens: rMd5 caused 100% mortality, a moderate level of tumor incidence in visceral organs and small visceral tumors; rMd5-Md5/CVI-Meq caused 100% mortality, a high level of tumor incidence in visceral organs, and very large visceral tumors; while rMd5-CVI/Md5-Meq caused an average of 37% mortality, rarely induced tumors in visceral organs, and the visceral tumors were small. In conclusion, our study suggests that the DNA-binding domain of Meq plays an essential role in transformation (tumor incidence), while the transcriptional regulatory domain of Meq influences the distribution and size of MDV-induced tumors.