JVI Accepts, published online ahead of print on 14 February 2007

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J. Virol. doi:10.1128/JVI.01524-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

Michael J. Keller, Allen W. Wu, Janet I. Andrews, Patrick W. McGonagill, Eric E. Tibesar, and Jeffery L. Meier^*

Departments of Internal Medicine; and Obstetrics and Gynecology, University of Iowa Carver College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52242

^* To whom correspondence should be addressed. Email: jeffery-meier{at}uiowa.edu.

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 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 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 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 interplay of multiple regulatory mechanisms. In contrast, MIE enhancer/promoter silence is not overcome by stimulation of the interferon- (IFN-) signaling pathway, despite the enhancer having two IFN--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.

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