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.