The avian Alphaherpesvirus, Marek’s disease virus (MDV) emerged as a major pathogen of poultry industry by the 1960s and has remained a serious concern worldwide. MDV has high infectivity with tropism for lymphocytes that causes dysfunction of host immune coordination. Hallmarks of MDV infection of chickens are paralysis, immune suppression, and rapid onset T-lymphomagenesis. The transformation of T-cells underlying Marek’s disease (MD) requires expression of the MDV-encoded, basic leucine zipper (bZIP) protein, Meq. MD is currently controlled by vaccination using live-attenuated, apathogenic vaccines. These vaccines, however, do not elicit sterilizing immunity, which has contributed to the emergence of increasingly virulent field strains. Mutations identified in the Meq coding sequence largely correlate with this virulence evolution. Conceivably, these amino acid substitutions affect specificity and promiscuity at the binding interface of transient protein-protein interactions that are intrinsic to cellular signaling mechanisms. I hypothesize that mutations in Meq have been selected by (1) the innate immune response elicited by host vaccination during the early lytic infection stage, and/or (2) changes in the Meq interactomes in latently infected T-cells. Using a gene-exchange strategy, a series of RB-1B-based recombinant-MDVs expressing Meq isoforms from prototype MDV pathotypes were constructed. To address this hypothesis, groups of unvaccinated, and in ovo vaccinated specific pathogen-free chickens were challenged at hatch with 2000 PFU of each of the recombinant viruses and pathogenicity was assessed based on the induction of lymphoproliferative lesions. The exchange of Meq isoforms demonstrate pathotype-specific trends in MD-incidence and -mortality rates, suggesting Meq has undergone functional selection through vaccine-mediated immune stimulation. In addition, I am examining the spatio-temporal interactomes of these Meq isoforms during lytic infection and in MDV-derived lymphoblastoid cell lines which serve to reveal the conserved cellular pathways that are targeted by viral proteins to facilitate MDV propagation and virulence during specific phases of infection.