When a virus infects a cell it tries to tweak the intracellular environment to favour virus replication. Exactly how viruses do this is not always clear. A recent paper in PNAS describes how Vaccinia virus makes its host cells feel “short of breath” by inducing a hypoxic-type intracellular response. This causes a metabolic change, shifting the host cell away from aerobic respiration. This is nice work and interesting stuff. The trouble is, we know that a number of other viruses seem to go to some trouble to avoid precisely the effect that Vaccinia virus is causing in order to boost aerobic glycolysis and oxidative phosphorylation. It’s fairly easy to imagine why they might want to do this, so exactly what benefit Vaccinia virus gains by doing precisely the opposite is … a mystery.
Got any ideas?
A mechanism for induction of a hypoxic response by vaccinia virus. Proc Natl Acad Sci 08 July 2013
Viruses have evolved sophisticated strategies to exploit host cell function for their benefit. Here we show that under physiologically normal oxygen levels (normoxia) vaccinia virus (VACV) infection leads to a rapid stabilization of hypoxia-inducible factor (HIF)-1α, its translocation into the nucleus and the activation of HIF-responsive genes, such as vascular endothelial growth factor (VEGF), glucose transporter-1, and pyruvate dehydrogenase kinase-1. HIF-1α stabilization is mediated by VACV protein C16 that binds the human oxygen sensing enzyme prolyl-hydroxylase domain containing protein (PHD)2 and thereby inhibits PHD2-dependent hydroxylation of HIF-1α. The binding between C16 and PHD2 is direct and specific, and ectopic expression of C16 alone induces transcription of HIF-1α responsive genes. Conversely, a VACV strain lacking the gene for C16, C16L, is unable to induce HIF-1α stabilization. Interestingly, the N-terminal region of C16 is predicted to have a PHD2-like structural fold but lacks the catalytic active site residues of PHDs. The induction of a hypoxic response by VACV is reminiscent of the biochemical consequences of solid tumor formation, and illustrates a poxvirus strategy for manipulation of cellular gene expression and biochemistry.