Functional Analysis of the Human Cytomegalovirus Ul82 Gene Product PP71 Protein During Virus Replication

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Functional Analysis of the Human Cytomegalovirus Ul82 Gene Product PP71 Protein During Virus Replication

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Title: Functional Analysis of the Human Cytomegalovirus Ul82 Gene Product PP71 Protein During Virus Replication
Author: Hagemeier, Stacy Cantrell
Abstract: Human cytomegalovirus (HCMV) is a beta-herpesvirus that infects the majority of the human population. Although primary infection is usually asymptomatic in immunocompetent individuals, HCMV infection can lead to severe disease in immunosuppressed individuals including neonates, transplant recipients, and AIDS patients. The HCMV UL82 gene encodes for the tegument protein pp71. It has previously been shown that pp71 is required for efficient virus replication at low multiplicities of infection and that it is a regulator of immediate-early gene expression. However, the mechanism whereby pp71 regulates IE gene expression and/or virus replication has not been elucidated. pp71 has also been shown to bind a number of cellular proteins including Rb familiy member proteins and the cellular protein hDaxx. This dissertation focused on determining if pp71's interaction with either of these proteins is important for viral replication and immediate-early gene expression in the context of a viral infection. We demonstrate that pp71's ability to target Rb family member proteins for degradation is not required for efficient viral replication. However, pp71's ability to interact with hDaxx is required for efficient viral replication and immediate-early gene expression. hDaxx has been identified as a transcriptional regulatory protein and is thought to regulate transcription through its interaction with histone deacetylases and core histones. This dissertation further defines the mechanism by which pp71 enhances viral replication by demonstrating that hDaxx functions to repress HCMV replication and IE gene expression. Importantly, we also demonstrated that the severe growth defect associated with the pp71 deletion mutant could be fully restored following infection of hDaxx knock-down cells. Experiments examining the mechanism by which pp71 relieves hDaxx mediated repression suggest that pp71 interacts with hDaxx to block histone deacetylase activity and therefore promotes the association of acetylated histones with viral immediate-early promoters. Taken together, these results demonstrate that pp71's interaction with hDaxx is critical for efficient virus replication and supports the hypothesis that pp71's interaction with hDaxx is important to "kick-start" the HCMV replication cycle by preventing host cell-mediated repression of viral immediate-early gene expression.
URI: http://hdl.handle.net/2152.5/443
Date: 2007-08-08

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