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Journal of Virology, October 2008, p. 9337-9344, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00603-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Downregulates Secretory Leukocyte Protease Inhibitor: a Novel Immune Evasion Mechanism {triangledown}

Esra Fakioglu,1 Sarah S. Wilson,1 Pedro M. M. Mesquita,1 Ehsan Hazrati,1,{dagger} Natalia Cheshenko,1 John A. Blaho,2,{ddagger} and Betsy C. Herold1*

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York,1 Mount Sinai School of Medicine, New York, New York2

Received 18 March 2008/ Accepted 16 July 2008

Secretory leukocyte protease inhibitor (SLPI), an anti-inflammatory mediator of mucosal immunity, inhibits human immunodeficiency virus (HIV) and herpes simplex virus (HSV) in cell culture. Epidemiological studies demonstrate that higher concentrations of SLPI in mucosal secretions are associated with a reduced risk of HIV transmission. The current studies were designed to test the hypothesis that HSV triggers a loss of SLPI to evade innate immunity and that this response may contribute to the increased risk of HIV infection in the setting of HSV infection. Exposure of human cervical epithelial cells to HSV-1 or HSV-2, but not HIV or vesicular stomatitis virus, triggered a significant and sustained reduction in SLPI levels. The reduction persisted when cells were infected in the presence of acyclovir but not following infection with UV-inactivated virus, indicating that viral gene expression, but not replication, is required. Reverse transcriptase PCR studies demonstrated that the loss of SLPI is mediated by downregulation of gene expression. SLPI downregulation was associated with activation of NF-{kappa}B signaling pathways and upregulation of proinflammatory cytokines, consistent with the known inhibitor effects of SLPI on NF-{kappa}B pathways. The downregulation mapped to viral early-gene expression, as variants impaired in expression of the ICP4 or ICP0 immediate-early gene failed to downregulate SLPI or activate NF-{kappa}B. Together, these results identify a novel role for HSV immediate-early-gene expression in regulating mucosal immune responses.

* Corresponding author. Mailing address: Albert Einstein College of Medicine, 1300 Morris Park Ave., Forchheimer 702, Bronx, NY 10467. Phone: (718) 430-2974. Fax: (718) 430-8627. E-mail: bherold{at}aecom.yu.edu

{triangledown} Published ahead of print on 30 July 2008.

{dagger} Present address: State University of New York, Upstate Medical University, Syracuse, NY.

{ddagger} Present address: Virology Research Division, MDL Corporation, Hamilton, NJ.

Journal of Virology, October 2008, p. 9337-9344, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00603-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nystrom, K., Norden, R., Muylaert, I., Elias, P., Larson, G., Olofsson, S. (2009). Induction of sialyl-Lex expression by herpes simplex virus type 1 is dependent on viral immediate early RNA-activated transcription of host fucosyltransferase genes. Glycobiology 19: 847-859 [Abstract] [Full Text]  


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