"Evolution of PKR antagonism in primate cytomegaloviruses"
The restriction factor Protein Kinase R (PKR) has been under strong positive selection through primate evolution, likely in response to constant challenges posed by viral antagonists. Rapid evolution of PKR has forced the cytomegalovirus (CMV) PKR antagonist TRS1 to evolve in parallel, resulting in two distinct mechanisms of PKR antagonism by Rhesus CMV (RhCMV) and Human CMV (HCMV). My preliminary data suggest that African Green Monkey CMV (AgmCMV), a close relative of RhCMV, recapitulates HCMV in its strategy to block the PKR pathway. I will determine if the TRS1 gene of AgmCMV is responsible for this phenotype. Additionally, the basis for the mechanistic differences among these CMVs and how they evolved remain undefined. To address these questions, I will construct Agm-RhCMV TRS1 chimeras and analyse their PKR antagonism properties. Moreover, I will perform a phylogenetic analysis of the US22 gene family, to which TRS1 belongs, to identify genes that have evolved under positive selection. I hypothesize that this will identify TRS1 and other potential PKR antagonists. Finally, I will use experimental evolution to test the hypothesis that gene amplification in response to changing host antiviral factors may be a driving force for the origins of the gene families of CMV. CMV is a frequent pathogen of immunocompromised cancer and AIDS patients, and is the leading cause of morbidity and mortality in transplant patients. This proposal will further our understanding of this essential viral factor and elucidate questions surrounding evolution of pathogenetic determinants in CMV.