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Journal of Virology, August 2008, p. 7666-7676, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.02274-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dengue Virus Replicon Expressing the Nonstructural Proteins Suffices To Enhance Membrane Expression of HLA Class I and Inhibit Lysis by Human NK Cells{triangledown}

Oren Hershkovitz,1 Alon Zilka,1 Ahuva Bar-Ilan,1 Shai Abutbul,1 Andrew Davidson,2 Michela Mazzon,3 Beate M. Kümmerer,4 Alon Monsoengo,1 Michael Jacobs,3 and Angel Porgador1*

Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel,1 Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom,2 Department of Infection, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom,3 Department of Virology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany4

Received 19 October 2007/ Accepted 16 May 2008

Many viruses escape the cellular immune response by downregulating cell surface expression of major histocompatibility complex (MHC) class I molecules. However, infection of cells with flaviviruses can upregulate the expression of these molecules. In this study we analyzed the expression of MHC class I in K562 and THP-1 human cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and express all the dengue virus nonstructural proteins together. We show that MHC class I expression is upregulated in the dengue virus replicon-expressing cells and that the binding of natural killer (NK) inhibitory receptors to these cells is augmented. This upregulation results in reduced susceptibility of the dengue virus replicon-expressing cells to NK lysis, indicating a possible mechanism for evasion of the dengue virus from NK cell recognition. Visualizing MHC class I expression in replicon-containing K562 and THP-1 cells by confocal microscopy demonstrated aggregation of MHC class I molecules on the cell surface. Finally, replicon-expressing K562 cells manifested increased TAP (transporter associated with antigen processing) and LMP (low-molecular-mass protein) gene transcription, while replicon-expressing THP-1 cells manifested increased NF-{kappa}B activity and MHC class I transcription. We suggest that expression of dengue virus nonstructural proteins is sufficient to induce MHC class I upregulation through both TAP-dependent and -independent mechanisms. Additionally, aggregation of MHC class I molecules on the cell membrane also contributes to significantly higher binding of low-affinity NK inhibitory receptors, resulting in lower sensitivity to lysis by NK cells.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Phone: 972-8-647-7283. Fax: 972-8-647-2574. E-mail: angel{at}bgu.ac.il

{triangledown} Published ahead of print on 28 May 2008.

Journal of Virology, August 2008, p. 7666-7676, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.02274-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hershkovitz, O., Rosental, B., Rosenberg, L. A., Navarro-Sanchez, M. E., Jivov, S., Zilka, A., Gershoni-Yahalom, O., Brient-Litzler, E., Bedouelle, H., Ho, J. W., Campbell, K. S., Rager-Zisman, B., Despres, P., Porgador, A. (2009). NKp44 Receptor Mediates Interaction of the Envelope Glycoproteins from the West Nile and Dengue Viruses with NK Cells. J. Immunol. 183: 2610-2621 [Abstract] [Full Text]  


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