Translational Control of Cytomegalovirus Gene Expression

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DESCRIPTION (provided by applicant): The long-range goals of this research are to elucidate mechanisms that regulate human cytomegalovirus (HCMV) gene expression at the translational level. Cells infected by HCMV continue to synthesize proteins, despite activation of host mechanisms designed to shut off translation and thereby prevent viral replication. These studies will clarify the biochemical and genetic basis for the preservation of the robust protein synthetic capacity in HCMV-infected cells. HCMV rescues replication of a vaccinia virus mutant lacking the double-stranded RNA binding protein gene E3L (VVdeltaE3L). In the absence of HCMV, cells infected with the VVdeltaE3L contain high levels of phosphorylated eIF2-alpha and RNaseL activity, and low levels of protein synthesis, viral late gene expression and viral production. HCMV infection reverses each of these properties. Using VVdeltaE3L as a means to activate the host cell antiviral responses, experiments will delineate the steps in the pathways leading to eIF2-alpha phosphorylation and RNaseL activation that are blocked by HCMV infection. The HCMV gene(s) responsible for the rescue of late gene expression and replication of VVdeltaE3L will be identified and its functional domains will be delineated. The mechanism of action of the complementing gene(s) will be elucidated and its expression properties, conservation among HCMV isolates and role in the replicative cycle will be determined. These studies will reveal new insights into the host-virus interactions that are likely to be critical determinants of the pathogenesis of HCMV disease.