NOVEL MECHANISMS OF TRANSCRIPTIONAL AND TRANSLATIONAL CONTROL OF HUMAN CYTOMEGALOVIRUS GENE EXPRESSION

Herpesvirus gene expression is dynamic and complex, with distinct complements of viral genes expressed at specific times in different infection contexts. These patterns of viral gene expression arise in part from the integration of multiple cellular and viral signals that affect the transcription and translation of viral genes. The use of alternative promoters provides an increased level of control, allowing different promoters to direct the transcription of the same gene in response to distinct temporal and contextual cues. While once considered rare, herpesvirus alternative promoter usage was recently found to be far more pervasive and impactful than previously thought. Here I show how host transcription factors Foxo3a and C/EBPβ differentially regulate alternative promoters to drive viral gene expression during human cytomegalovirus (HCMV) reactivation. At the post-transcriptional level, HCMV protein pTRS1 further modulates viral gene expression by antagonizing antiviral kinase PKR at multiple junctures. I describe a novel interaction of pTRS1 with cellular phosphatase PP1 to further enhance the effect of pTRS1 on inhibiting host antiviral responses. My work indicates that these strategies for nuanced control of viral gene expression is a crucial component of herpesvirus transcriptional and post-transcriptional gene regulation.Doctor of Philosoph