Human cytomegalovirus (HCMV) infections are very common and result in life-threatening diseases in newborns and immunocompromised patients. As well, HCMV provides a useful model system for studies of the regulation of eukaryotic gene expression at the translational level. Studies in the Geballe lab aim to clarify the biochemical and genetic basis for the preservation of protein synthetic capacity of cells infected with HCMV and related viruses. Our experiments have identified genes of several different cytomegaloviruses that are capable of blocking a key cellular defense system that is designed to sense double-stranded RNA produced in infected cells and shut off protein synthesis. The proteins encoded by these viral genes act in part through an unconventional double-stranded RNA binding domain but additional domains of uncertain function are also necessary. Efforts are now underway to determine the mechanism by which these genes act to block antiviral responses and to determine their roles during HCMV replication. Additional research efforts utilize evolutionary analyses to guide studies of mechanisms by which other viruses, such as vaccinia virus, block various host defense systems, especially those that sense and respond to double-stranded RNA. 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. Dr. Geballe collaborates with Drs. Boeckh, Corey, Englund, Gantt, and Jerome.
Vieira J, Schall TJ, Corey L and Geballe AP. Functional analysis of the human cytomegalovirus US28 gene by insertion mutagenesis with the green fluorescence protein gene. J Virol 72:8158-8165, 1998.
Child SJ, Miller MK, and Geballe AP. Cell type-dependent and -independent control of HER-2/neu translation. Int J Biochem Cell Biol 31:201-213, 1999.
Child SJ, Miller MK, and Geballe AP. Translational control by an upstream open reading frame in the HER-2/neu transcript. J Biol Chem 274:24335-24341, 1999.
Alderete JP, Jarrahian S, and Geballe AP. Translational effects of mutations and polymorphisms in a repressive upstream open reading frame of the human cytomegalovirus UL4 gene. J Virol 73:8330-8337, 1999.
Landini MP, Lazzarotto T, Xu J, Geballe AP, and Mocarski ES. Humoral immune response to proteins of human cytomegalovirus latency-associated transcripts. Biol Blood Marrow Transplant 6:100-108, 2000.
Geballe AP and Sachs MS. Translational control by upstream open reading frames. In Translational Control of Gene Expression N. Sonenberg, J.W.B. Hershey, and M.B. Matthews, eds., Cold Spring Harbor Press. p595-614, 2000.