Human cytomegalovirus (HCMV), a member of the herpesvirus family, is the leading viral cause of birth defects and causes significant morbidity and mortality in immunosuppressed individuals. The multiple pathogenic effects of HCMV are likely manifested through a complex interplay of viral gene products and induced and repressed cellular functions. HCMV immediate early (IE) and early gene expression clearly play a pivotal role in this scheme. A major part of our research has been directed towards determining the cis-acting regulatory elements and the cellular and viral factors involved in the regulation of HCMV early gene expression, with primary focus on the promoter for the ULI 12-113 RNAs. We have also studied in great depth the functional properties of the major viral transactivator of these genes, 1E2 86, and have developed a way to generate viruses with mutations in the 1E2 86 gene. In this renewal application, we propose to continue our studies on 1E2 86 function and on the cellular and viral factors governing HCMV early gene expression. The approach is to couple functional in vivo genetic analyses with biochemical and molecular assays to achieve the following aims: 1) determination of the function of the 1E2 86 protein in the context of the viral genome; 2) elucidation of 1E2 86-mediated effects on expression of cellular genes with focus on genes involved in cell cycle control, transcriptional regulation, apoptosis, and tumor suppression; and 3) determination of the mechanism of regulation of early viral gene expression by viral and cellular factors, using the UL1 12-113 gene as a model. The long range goals of this research are to define at the molecular level the mechanisms which operate to control HCMV gene expression, thus providing an important foundation for understanding how the complex interactions of viral and host functions relate to the pathogenesis of the virus.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology Study Section (VR)
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Daschner, Phillip J
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Clark, Elizabeth; Spector, Deborah H (2015) Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, J Virol 89:6928-39
Strang, Blair L; Bender, Brian J; Sharma, Mayuri et al. (2012) A mutation deleting sequences encoding the amino terminus of human cytomegalovirus UL84 impairs interaction with UL44 and capsid localization. J Virol 86:11066-77
DuRose, Jenny B; Li, Julie; Chien, Shu et al. (2012) Infection of vascular endothelial cells with human cytomegalovirus under fluid shear stress reveals preferential entry and spread of virus in flow conditions simulating atheroprone regions of the artery. J Virol 86:13745-55
Burgdorf, Sarah W; Clark, Charles L; Burgdorf, James R et al. (2011) Mutation of glutamine to arginine at position 548 of IE2 86 in human cytomegalovirus leads to decreased expression of IE2 40, IE2 60, UL83, and UL84 and increased transcription of US8-9 and US29-32. J Virol 85:11098-110
Tran, Karen; Mahr, Jeffrey A; Spector, Deborah H (2010) Proteasome subunits relocalize during human cytomegalovirus infection, and proteasome activity is necessary for efficient viral gene transcription. J Virol 84:3079-93
Tran, Karen; Kamil, Jeremy P; Coen, Donald M et al. (2010) Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1. J Virol 84:10832-43
Sanders, Rebecca L; Spector, Deborah H (2010) Human cytomegalovirus IE2 86 and IE2 40 proteins differentially regulate UL84 protein expression posttranscriptionally in the absence of other viral gene products. J Virol 84:5158-70
Kapasi, Anokhi J; Clark, Charles L; Tran, Karen et al. (2009) Recruitment of cdk9 to the immediate-early viral transcriptosomes during human cytomegalovirus infection requires efficient binding to cyclin T1, a threshold level of IE2 86, and active transcription. J Virol 83:5904-17
Kapasi, Anokhi J; Spector, Deborah H (2008) Inhibition of the cyclin-dependent kinases at the beginning of human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome. J Virol 82:394-407
Sanders, Rebecca L; Clark, Charles L; Morello, Christopher S et al. (2008) Development of cell lines that provide tightly controlled temporal translation of the human cytomegalovirus IE2 proteins for complementation and functional analyses of growth-impaired and nonviable IE2 mutant viruses. J Virol 82:7059-77

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