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Induction of MHC Class I HLA-A2 promoter by dengue virus occurs at the NFκB binding domains of the Class I Regulatory Complex.

Abstract
Despite aggressive efforts in dengue research, the control of dengue diseases and discovery of therapeutics against them await complete elucidation of its complex immune-pathogenesis. Unlike many viruses that escape the host's immune responses by suppressing the major histocompatibility complex (MHC) Class I pathway, many Flaviviruses up-regulate the cell surface expression of MHC Class I complex. We recently reported MHC Class I HLA-A2 promoter activation by all serotypes of dengue virus (DV). The mechanism by which DV regulates this is further explored here in HepG2 human liver cell line. Using real-time PCR, evidence that, similar to infections by other Flaviviruses, DV infection has the ability to up-regulate the MHC Class I transcription and mRNA synthesis, is presented. The region responsive towards DV infection of all serotypes was mapped to the Class I Regulatory Complex (CRC) of the HLA-A2 promoter. Competition electrophoretic mobility shift assay (EMSA) with NFκB probe established the presence of specific DNA-protein complex in DV-infected nuclear extracts. Antibody-supershift assays identified the MHC Class I promoter activation by DV to occur through binding of p65/p50 heterodimers and p65 homodimers to κB1 and κB2 cis-acting elements, respectively, within the CRC, and not with the interferon consensus sequence (ICS). This study presents evidence of MHC Class I gene modulation by DV, hence providing a better understanding of dengue immune-pathogenesis that would consequently facilitate the discovery of antiviral therapeutics against dengue.
AuthorsShatrah Othman, Noorsaadah Abd Rahman, Rohana Yusof
JournalVirus research (Virus Res) Vol. 163 Issue 1 Pg. 238-45 (Jan 2012) ISSN: 1872-7492 [Electronic] Netherlands
PMID22001567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier B.V. All rights reserved.
Chemical References
  • HLA-A2 Antigen
  • NF-kappa B
  • DNA
Topics
  • DNA (metabolism)
  • Dengue Virus (immunology)
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Profiling
  • HLA-A2 Antigen (biosynthesis, genetics)
  • Hep G2 Cells
  • Hepatocytes (immunology, virology)
  • Humans
  • NF-kappa B (metabolism)
  • Promoter Regions, Genetic
  • Protein Binding
  • Real-Time Polymerase Chain Reaction
  • Transcriptional Activation

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