All ETDs from UAB

Advisory Committee Chair

Mark N Prichard

Advisory Committee Members

Etty Benveniste

William J Britt

Jacqueline N Parker

Elizabeth S Sztul

Sunnie R Thompson

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Human cytomegalovirus (CMV) infection results in destructive infections in neonates and immunocompromised individuals. Being the primary congenital infection in the United States, it can often result in permanent neurological deficits in infants. The current therapies for CMV infections all target the viral DNA polymerase and also have dose-limiting toxicities. Isolates resistant to ganciclovir (GCV), the therapy of choice, can sometimes overwhelm immunocompromised hosts. Better therapies for this infection are required. The CMV UL97 kinase is a key enzyme in the treatment of CMV infection because it phosphorylates GCV. Additionally, maribavir (MBV) specifically inhibits UL97 kinase activity and inhibits viral replication. Recombinant viruses deficient for UL97 kinase activity do not replicate well in vitro. Studies using MBV in wild-type infections complement genetic studies and provide a very powerful tool to confirm results for the recombinant viruses. The aims of this research seek to further expound the functions of CMV UL97 kinase, and have the potential to identify novel antiviral therapies. Early studies have identified cyclin-dependent kinase (CDK)-like characteristics of this enzyme. UL97 kinase shares many targets with CDK, and our research pinpointed another common target, retinoblastoma protein (RB). Like CDKs, UL97 kinase can hyperphosphorylate and inactivate RB, which is a unique mechanism of RB regulation by a virus. Studies in viruses utilizing homologous proteins to pUL97 suggest that it not only phosphorylates other CDK targets, but also dysregulates CDKs themselves. We hypothesized that CMV UL97 kinase is a major modifier of host cell cycle checkpoint regulators to promote viral replication by regulating both CDKs and CDK targets. Mutational analyses of pUL97 indicated that the amino-terminal putative RB-binding motif was important for RB hyperphosphorylation, and disruption of this domain rendered the virus hypersensitive to MBV. We also characterized changes in G2-M checkpoint regulation induced by UL97 kinase activity, and showed that the kinase was involved in the upregulation of CDK1 and other mitotic regulators within the infected cell.



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