Human cytomegalovirus (HCMV) infections are very common and result in life-threatening diseases in newborns and immunocompromised patients. As well, HCMV provides a valuable model system for studies of regulation of eukaryotic gene expression at the translational level. After infection by many viruses, including HCMV, cells continue to synthesize proteins despite activation of host cell responses designed to shut off translation and thereby prevent viral replication. Studies in the Geballe lab have identified genes in HCMV and related viruses that are capable of blocking antiviral responses, especially those activated by double-stranded RNA. The proteins encoded by the HCMV genes act in part through an unconventional double-stranded RNA binding domain. As well, they self-associate and bind to the critical cellular kinase PKR and to other host and viral factors. Efforts are now underway to determine the origin of the activators of PKR produced during HCMV infection and to elucidate the mechanisms by which the viral genes block the antiviral responses. As well, new experiments are underway to clarify how cytomegalovirus antagonists evolved and have contributed to the rapid adaptation of PKR during primate evolution.
Another line of research aims to identify the genes and mechanisms by which poxviruses evade PKR and related host dsRNA-activated anti-viral pathways. These studies should reveal new insights into the host-virus interactions that are likely to be key determinants of the pathogenesis of viral infections and may have implications for the design of viral vaccines and vectors.
Child, SJ, Brennan G, Braggin JE, Geballe AP. Species specificity of protein kinase R antagonism by cytomegalovirus TRS1 genes. J Virol. 2012; 86(22): 3880-9.
• NCBI Abstract
Elde, NC, Child SJ , Eickbush MT, Kitzman JO, Rogers KS, Shendure J, Geballe AP, Malik HS. Poxviruses deploy genomic accordions to adapt rapidly against antiviral defenses. Cell. 2012; 150(4): 831-41.
• PubMed Abstract
Bierle, CJ, Schleiss MR, and Geballe AP. Antagonism of the protein kinase R pathway by the guinea pig cytomegalovirus US22-family gene gp145. Virology. 2012; 433(1): 157-166.
• PubMed Abstract