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Journal of Virology, December 2004, p. 12788-12799, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12788-12799.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of the Proximal Enhancer of the Major Immediate-Early Promoter in Human Cytomegalovirus Replication

Hiroki Isomura,1,2 Tatsuya Tsurumi,2 and Mark F. Stinski1*

Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa,1 Division of Virology, Aichi Cancer, Center Research Institute, Chikusa-ku, Nagoya, Japan2

Received 16 July 2004/ Accepted 19 July 2004

The human cytomegalovirus (CMV) enhancer has a distal component (positions –550 to –300) and a proximal component (–300 to –39) relative to the transcription start site (+1) of the major immediate-early (MIE) promoter. Without the distal enhancer, human CMV replicates slower and has a small-plaque phenotype. We determined the sequence requirements of the proximal enhancer by making 5'-end deletions to positions –223, –173, –116, –67, and –39. Even though recombinant virus with the proximal enhancer deleted to –39 has the minimal TATA box-containing MIE promoter element, it cannot replicate independently in human fibroblast cells. Recombinant virus with a deletion to –67 has an Sp-1 transcription factor binding site which may represent a minimal enhancer element for recombinant virus replication in human fibroblast cells. Although recombinant virus with a deletion to –223 replicates to titers at least 100-fold less than that of the wild-type virus, it replicates to titers 8-fold higher than that of recombinant virus with a deletion to –173 and 20-fold higher than that of virus with a deletion to –67. Recombinant virus with a deletion to –173 replicates more efficiently than that with a deletion to –116. There was a direct correlation between the level of infectious virus replication and time after infection, amount of MIE gene transcription, MIE and early viral protein synthesis, and viral DNA synthesis. The extent of the proximal enhancer determines the efficiency of viral replication.

* Corresponding author. Mailing address: Department of Microbiology, Carver College of Medicine, 3-772 BSB, University of Iowa, Iowa City, IA 52242. Phone: (319) 335-7792. Fax: (319) 335-9006. E-mail: mark-stinski{at}uiowa.edu.

Journal of Virology, December 2004, p. 12788-12799, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12788-12799.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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