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Journal of Virology, June 2005, p. 7438-7452, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7438-7452.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Exon 3 of the Human Cytomegalovirus Major Immediate-Early Region Is Required for Efficient Viral Gene Expression and for Cellular Cyclin Modulation

Elizabeth A. White1 and Deborah H. Spector2*

Division of Biological Sciences,1 Department of Cellular and Molecular Medicine, Center for Molecular Genetics, and School of Pharmacy, University of California, San Diego, La Jolla, California 920932

Received 15 December 2004/ Accepted 1 March 2005

The human cytomegalovirus (HCMV) major immediate-early (IE) proteins share an 85-amino-acid N-terminal domain specified by exons 2 and 3 of the major IE region, UL122-123. We have constructed IE {Delta}30-77, a recombinant virus that lacks the majority of IE exon 3 and consequently expresses smaller forms of both IE1 72- and IE2 86-kDa proteins. The mutant virus is viable but growth impaired at both high and low multiplicities of infection and exhibits a kinetic defect that is not rescued by growth in fibroblasts expressing IE1 72-kDa protein. The kinetics of mutant IE2 protein accumulation in IE {Delta}30-77 virus-infected cells are approximately normal compared to wild-type virus-infected cells, but the IE {Delta}30-77 virus is delayed in expression of early viral genes, including UL112-113 and UL44, and does not sustain expression of mutant IE1 protein as the infection progresses. Additionally, cells infected with IE {Delta}30-77 exhibit altered expression of cellular proteins compared to wild-type HCMV-infected cells. PML is not dispersed but is retained at ND10 sites following infection with IE {Delta}30-77 mutant virus. While the deletion mutant retains the ability to mediate the stabilization of cyclin B1, cdc6, and geminin in infected cells, its capacity to upregulate the expression of cyclin E has been reduced. These data indicate that the activity of one or both of the HCMV major IE proteins is required in vivo for the modulation of cell cycle proteins observed in cells infected with wild-type HCMV.

* Corresponding author. Mailing address: Dept. of Cellular and Molecular Medicine, Center for Molecular Genetics, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Phone: (858) 534-4584. Fax: (858) 534-6083. E-mail: dspector{at}ucsd.edu.

Journal of Virology, June 2005, p. 7438-7452, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7438-7452.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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