Human cytomegalovirus is the prototypical member of the beta-herpesvirus family. Seroepidemiologic studies have shown that human cytomegalovirus infection is widespread in the human population. 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 and a life-threatening adventitious agent in transplant recipients and AIDS patients. The long-term objective of this research program is to elucidate the function of human cytomegalovirus genes that regulate the interaction of the virus with its host cell and thereby control the processes of viral replication and pathogenesis. This proposal will study human cytomegalovirus proteins that are delivered to the cell as constituents of the virion. These proteins have the potential to exert profound effects on the virus-host interaction, because they are present at the very start of the infectious process.
My specific aims follow: (1) Investigate the function and biochemical activities of the UL83-coded pp65 protein; (2) Investigate the function and biochemical activities of the UL69 protein. (3) Investigate the function and biochemical activities of the UL32-coded pp150 protein. (4) Investigate the function and biochemical activities of the UL48 protein. Our studies will include analysis of both a laboratory strain (AD169) and a clinical isolate (VR1814, FIX) of the virus.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082396-07
Application #
6911764
Study Section
Virology Study Section (VR)
Program Officer
Daschner, Phillip J
Project Start
1999-09-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
7
Fiscal Year
2005
Total Cost
$368,955
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
Purdy, John G; Shenk, Thomas; Rabinowitz, Joshua D (2015) Fatty acid elongase 7 catalyzes lipidome remodeling essential for human cytomegalovirus replication. Cell Rep 10:1375-85
Sharon-Friling, Ronit; Shenk, Thomas (2014) Human cytomegalovirus pUL37x1-induced calcium flux activates PKC?, inducing altered cell shape and accumulation of cytoplasmic vesicles. Proc Natl Acad Sci U S A 111:E1140-8
Mathias, Rommel A; Greco, Todd M; Oberstein, Adam et al. (2014) Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 159:1615-25
Grady, Sarah L; Purdy, John G; Rabinowitz, Joshua D et al. (2013) Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection. Proc Natl Acad Sci U S A 110:E5006-15
Koyuncu, Emre; Purdy, John G; Rabinowitz, Joshua D et al. (2013) Saturated very long chain fatty acids are required for the production of infectious human cytomegalovirus progeny. PLoS Pathog 9:e1003333
Lee, Song Hee; Kalejta, Robert F; Kerry, Julie et al. (2012) BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection. Proc Natl Acad Sci U S A 109:9575-80
Gudleski-O'Regan, Nicole; Greco, Todd M; Cristea, Ileana M et al. (2012) Increased expression of LDL receptor-related protein 1 during human cytomegalovirus infection reduces virion cholesterol and infectivity. Cell Host Microbe 12:86-96
Grady, Sarah L; Hwang, Jesse; Vastag, Livia et al. (2012) Herpes simplex virus 1 infection activates poly(ADP-ribose) polymerase and triggers the degradation of poly(ADP-ribose) glycohydrolase. J Virol 86:8259-68
O'Connor, Christine M; Shenk, Thomas (2012) Human cytomegalovirus pUL78 G protein-coupled receptor homologue is required for timely cell entry in epithelial cells but not fibroblasts. J Virol 86:11425-33
Terry, Laura J; Vastag, Livia; Rabinowitz, Joshua D et al. (2012) Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection. Proc Natl Acad Sci U S A 109:3071-6

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