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Journal of Virology, January 2002, p. 313-326, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.313-326.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Requirement of Multiple cis-Acting Elements in the Human Cytomegalovirus Major Immediate-Early Distal Enhancer for Viral Gene Expression and Replication

Jeffery L. Meier,1,2* Michael J. Keller,1 and James J. McCoy1

Department of Internal Medicine and the Helen C. Levitt Center for Viral Pathogenesis and Disease, University of Iowa College of Medicine, Iowa City, Iowa, 52242,1 Department of Veterans Affairs Medical Center, Iowa City, Iowa 522462

Received 10 July 2001/ Accepted 25 September 2001

We have shown previously that the human cytomegalovirus (HCMV) major immediate-early (MIE) distal enhancer is needed for MIE promoter-dependent transcription and viral replication at low multiplicities of infection (MOI). To understand how this region works, we constructed and analyzed a series of HCMVs with various distal enhancer mutations. We show that the distal enhancer is composed of at least two parts that function independently to coordinately activate MIE promoter-dependent transcription and viral replication. One such part is contained in a 47-bp segment that has consensus binding sites for CREB/ATF, SP1, and YY1. At low MOI, these working parts likely function in cis to directly activate MIE gene expression, thus allowing viral replication to ensue. Three findings support the view that these working parts are likely cis-acting elements. (i) Deletion of either part of a bisegmented distal enhancer only slightly alters MIE gene transcription and viral replication. (ii) Reversing the distal enhancer’s orientation largely preserves MIE gene transcription and viral replication. (iii) Placement of stop codons at -300 or -345 in all reading frames does not impair MIE gene transcription and viral replication. Lastly, we show that these working parts are dispensable at high MOI, partly because of compensatory stimulation of MIE promoter activity and viral replication that is induced by a virion-associated component(s) present at a high viral particle/cell ratio. We conclude that the distal enhancer is a complex multicomponent cis-acting region that is required to augment both MIE promoter-dependent transcription and HCMV replication.

* Corresponding author. Mailing address: Department of Internal Medicine, University of Iowa College of Medicine, 3-750 Bowen Science Building, 51 Newton Rd., Iowa City, IA 52242. Phone: (319) 356-7055. Fax: (319) 335-9006. E-mail: jeffery-meier{at}uiowa.edu.

Journal of Virology, January 2002, p. 313-326, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.313-326.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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