Control of Translation in Herpesvirus Infected Cells

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Regulation of gene expression at the level of translation is fundamentally important for the control of normal cell growth, development, differentiation, learning, memory, and the response to environmental stress, including viral infection. In particular, the translation of many eukaryotic capped, polyadenylated mRNAs is controlled at the initiation step, where the regulated assembly of a specialized, multiprotein complex is required to recruit the small ribosome subunit to the mRNA 5' terminus. The translation initiation factor components of this complex are capable of responding to different cellular signaling cascades, enabling a rapid response to diverse physiological effectors. Viral model systems have proven to be particularly useful in elaborating cellular translational control strategies because their successful replication absolutely requires viral mRNA translation. In their continued efforts to capture and engage the cellular protein synthesis machinery, viruses must effectively control the cellular signaling cascades that regulate translation. This investigation utilizes a herpes virus family member, human cytomegalovirus (HCMV), as a probe to explore the complex circuitry regulating the initiation of mRNA translation. Although innocuous in most healthy individuals, HCMV is a widespread, opportunistic pathogen responsible for severe disease among the immunocompromised, including bone marrow and solid organ transplant recipients along with AIDS patients. In addition, congenital HCMV infection is the leading viral cause of birth defects in newborns. Our long-term overall objective is to understand how HCMV manipulates cellular translational control pathways to ensure that viral mRNAs can compete effectively with cellular mRNAs for access to translation initiation factors. As this process is critical for productive replication and reactivation from latency, our investigation is likely to reveal new targets for interfering with viral replication and new strategies for creating weakened, attenuated strains useful for vaccine development. In addition, these studies will provide insight into basic mechanisms of translational control that are likely to prove important in many human diseases, including cancer and diabetes, where the regulation of protein production is abnormal. We specifically propose to i) determine how HCMV infection affects eIF4F-core and associated components; ii) define the mechanism(s) by which PABP abundance is controlled translationally in HCMV-infected cells; and iii) evaluate the role of cellular eIF4E-kinases & eIF4E phosphorylation on viral replication & pathogenesis