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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

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-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.

Published ahead of print on 28 May 2008.