Hypoxia enhances antibody-dependent dengue virus infection

EMBO J. 2017 May 15;36(10):1348-1363. doi: 10.15252/embj.201695642. Epub 2017 Mar 20.


Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post-mortem analysis. These organs are known to have low oxygen levels (~0.5-4.5% O2) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia-induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O2 show greater susceptibility to antibody-dependent enhancement of DENV infection. Low oxygen level induces HIF1α-dependent upregulation of fragment crystallizable gamma receptor IIA (FcγRIIA) as well as HIF1α-independent alterations in membrane ether lipid concentrations. The increased FcγRIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody-dependent but hypoxia-induced and suggest a role for targeting hypoxia-induced factors for anti-dengue therapy.

Keywords: Fc receptors; antibody‐dependent enhancement; cellular lipids; dengue; hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Viral / metabolism*
  • Antibody-Dependent Enhancement*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Dengue / pathology*
  • Dengue Virus / growth & development*
  • Humans
  • Hypoxia*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lipid Metabolism
  • Monocytes / virology*
  • Receptors, IgG / metabolism


  • Antibodies, Viral
  • Fc gamma receptor IIA
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, IgG