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Journal of Virology, June 2007, p. 6669-6681, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.01524-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Reversal of Human Cytomegalovirus Major Immediate-Early Enhancer/Promoter Silencing in Quiescently Infected Cells via the Cyclic AMP Signaling Pathway{triangledown}

Michael J. Keller,1 Allen W. Wu,1 Janet I. Andrews,2 Patrick W. McGonagill,3 Eric E. Tibesar,3 and Jeffery L. Meier1,3*

Departments of Internal Medicine,1 Obstetrics and Gynecology, University of Iowa Carver College of Medicine,2 Veterans Affairs Medical Center, Iowa City, Iowa 522423

Received 17 July 2006/ Accepted 2 February 2007

The human cytomegalovirus (HCMV) major immediate-early (MIE) enhancer contains five functional cyclic AMP (cAMP) response elements (CRE). Because the CRE in their native context do not contribute appreciably to MIE enhancer/promoter activity in lytically infected human fibroblasts and NTera2 (NT2)-derived neurons, we postulated that they might have a role in MIE enhancer/promoter reactivation in quiescently infected cells. Here, we show that stimulation of the cAMP signaling pathway by treatment with forskolin (FSK), an adenylyl cyclase activator, greatly alleviates MIE enhancer/promoter silencing in quiescently infected NT2 neuronal precursors. The effect is immediate, independent of de novo protein synthesis, associated with the phosphorylation of ATF-1 serine 63 and CREB serine 133, dependent on protein kinase A (PKA) and the enhancer's CRE, and linked to viral-lytic-cycle advancement. Coupling of FSK treatment with the inhibition of either histone deacetylases or protein synthesis synergistically activates MIE gene expression in a manner suggesting that MIE enhancer/promoter silencing is optimally relieved by an interplay of multiple regulatory mechanisms. In contrast, MIE enhancer/promoter silence is not overcome by stimulation of the gamma interferon (IFN-{gamma}) signaling pathway, despite the enhancer having two IFN-{gamma}-activated-site-like elements. We conclude that stimulation of the cAMP/PKA signaling pathway drives CRE-dependent MIE enhancer/promoter activation in quiescently infected cells, thus exposing a potential mode of regulation in HCMV reactivation.

* Corresponding author. Mailing address: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242. Phone: (319) 335-7906. Fax: (319) 335-9006. E-mail: jeffery-meier{at}uiowa.edu

{triangledown} Published ahead of print on 14 February 2007.

Journal of Virology, June 2007, p. 6669-6681, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.01524-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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