Regulation of Gammaherpesviral Late Gene Expression

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 DESCRIPTION (provided by applicant): Herpesviruses are endemic within the human population, and cause a wide range of life-threatening diseases. Members of the beta-herpesvirus (β-HV) and gamma-herpesvirus (γ-HV) subfamilies are extremely problematic in immunocompromised individuals, leading to severe congenital disorders and a variety of cancers. During the herpesviral replication cycle, viral genes are expressed temporally in an ordered cascade, with timing linked to appropriate life cycle stage needs. Following viral genome replication, a group of viral genes termed late genes (L) are robustly activated and produce proteins necessary for progeny virion assembly and egress. Mechanisms governing L gene expression in the β-HV and the γ-HV largely remain a mystery. However, shedding light on this aspect of herpesviral biology has become a high priority, in part due to recent discoveries demonstrating that mutants impaired in this final viral transcription cascade cannot produce progeny virions. An understanding of the regulatory features critical for L gene transcription may therefore reveal robust new targets for antiviral strategies. Our data demonstrate that late gene transcriptional regulation is unique, as it incorporates both molecular mimicry and selective recruitment of key host transcriptional machinery in a manner not previously observed in viral or host gene expression. Thus, the focus of this grant is to define the composition and regulation of this novel gene expression complex, as well as reveal how it may globally impact gene expression in infected cells.