Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells

J Virol. 2008 Aug;82(15):7666-76. doi: 10.1128/JVI.02274-07. Epub 2008 May 28.

Abstract

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-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / biosynthesis
  • Cell Line
  • Cell Membrane / chemistry
  • Cytotoxicity Tests, Immunologic
  • Cytotoxicity, Immunologic*
  • Dengue Virus / immunology*
  • Histocompatibility Antigens Class I / biosynthesis*
  • Humans
  • Killer Cells, Natural / immunology*
  • Microscopy, Confocal
  • NF-kappa B / metabolism
  • Viral Nonstructural Proteins / immunology*

Substances

  • ATP-Binding Cassette Transporters
  • Histocompatibility Antigens Class I
  • NF-kappa B
  • Viral Nonstructural Proteins
  • transporter associated with antigen processing (TAP)