Herpes simplex virus-mediated regulation of host gene expression

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Project summary: Herpes simplex virus 1 (HSV-1) is a highly contagious pathogen that causes a number of diseases ranging from painful skin lesions to keratitis and encephalitis. The gene expression program of HSV-1 has been extensively studied for the past several decades. Despite the intensive effort, however, it remains unclear how HSV-1 suppresses host gene expression to allow efficient viral replication. Genetic studies have demonstrated that ICP27, encoded by an essential immediate early gene, plays an essential role in the inhibition of host mRNA biogenesis. Based on in vitro assays, earlier studies have suggested that ICP27 blocks transcription and splicing of host genes. Through high throughput analyses of host gene expression following HSV-1 infection or ICP27 overexpression, however, recent studies detected no global inhibition of either transcription or splicing, but only splicing changes in a small number of genes. Interestingly, these studies found that there was widespread transcription termination defect in HSV-1-infected cells and that this inhibition was specific to host genes. Although these recent studies provided important insight into HSV-1-induced host shutoff, the molecular mechanisms underlying HSV-1-mediated block of transcription termination remain completely unknown and it is unclear whether such a block is required for efficient viral replication. We aim to address these important questions in this proposal. In our preliminary studies, we found that ICP27 specifically interacts with the essential mRNA 3' processing factor CPSF and that ICP27 blocks mRNA 3' processing. Since mRNA 3' processing is required for transcription termination, we will test the hypothesis that ICP27 inhibits host transcription termination by blocking mRNA 3' processing via CPSF, and that ICP27-mediated disruption of host mRNA processing is important for HSV replication.