Human cytomegalovirus (HCMV) is the prototypical member of the beta-herpesvirus family. Epidemiological studies have shown that HCMV infection is widespread. In healthy individuals infection is generally asymptomatic, but the virus can cause serious disease in people with immature or compromised immune systems. It is the leading infectious disease cause of birth defects (primarily hearing loss) and a life- threatening adventitious agent in transplant recipients. The long-term objective of this research program is to elucidate the function of HCMV genes that regulate the interaction of the virus with its host cell and thereby control viral replication and pathogenesis. This proposal will study HCMV immediate-early gene products. These proteins and RNAs have the potential to exert profound effects on the virus-host interaction, because they are present at the very start of the infectious process. This is a renewal application that builds on our recent progress, which indicates that the UL123-coded IE1 protein controls the acetylation of proteins, reveals that the IRS1/TRS1 proteins have profound effects on the expression of viral mRNAs, and demonstrates that the so-called 5kb RNA is a stable intron. I now propose to extend these observations.
My specific aims i nvestigate the function and biochemical activities of (1) the HCMV UL122-coded IE1 protein; (2) the HCMV IRS1/TRS1 proteins;and (3) the HCMV 5kb transcript domain and its MCMV orthologue, the 7.2kb transcript domain. This project will include analysis of a laboratory strain (AD169) and a clinical isolate (VR1814, FIX) of HCMV. HCMV replication will be studied in fibroblasts, the cell commonly used to propagate HCMV;endothelial cells and epithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085786-10
Application #
7748003
Study Section
Virology - A Study Section (VIRA)
Program Officer
Daschner, Phillip J
Project Start
2000-04-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
10
Fiscal Year
2010
Total Cost
$299,209
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Teng, Melissa W; Bolovan-Fritts, Cynthia; Dar, Roy D et al. (2012) An endogenous accelerator for viral gene expression confers a fitness advantage. Cell 151:1569-80
Hargett, Danna; Shenk, Thomas E (2010) Experimental human cytomegalovirus latency in CD14+ monocytes. Proc Natl Acad Sci U S A 107:20039-44
Aoyagi, Mariko; Gaspar, Miguel; Shenk, Thomas E (2010) Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1. Proc Natl Acad Sci U S A 107:2640-5
Moorman, Nathaniel J; Shenk, Thomas (2010) Rapamycin-resistant mTORC1 kinase activity is required for herpesvirus replication. J Virol 84:5260-9
Moorman, Nathaniel J; Sharon-Friling, Ronit; Shenk, Thomas et al. (2010) A targeted spatial-temporal proteomics approach implicates multiple cellular trafficking pathways in human cytomegalovirus virion maturation. Mol Cell Proteomics 9:851-60
Cristea, Ileana M; Moorman, Nathaniel J; Terhune, Scott S et al. (2010) Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J Virol 84:7803-14
Terhune, Scott S; Moorman, Nathaniel J; Cristea, Ileana M et al. (2010) Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA. PLoS Pathog 6:e1000965
Womack, Andrew; Shenk, Thomas (2010) Human cytomegalovirus tegument protein pUL71 is required for efficient virion egress. MBio 1:
Mitchell, Dora P; Savaryn, John P; Moorman, Nathaniel J et al. (2009) Human cytomegalovirus UL28 and UL29 open reading frames encode a spliced mRNA and stimulate accumulation of immediate-early RNAs. J Virol 83:10187-97
Schroer, Jorg; Shenk, Thomas (2008) Inhibition of cyclooxygenase activity blocks cell-to-cell spread of human cytomegalovirus. Proc Natl Acad Sci U S A 105:19468-73

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