In the context of severe pneumonia caused by infection with highly pathogenic influenza virus, HIF-1 induction by both tissue hypoxia, due to compromised respiratory capacity, and the cytokine cascade initiated by innate immune responses, notably IFN-α/β, would be possible [28, 39, 40] . Pulsoximetry was not carried out in the present study due to logistic constraints, and thus it is not possible to determine with certainty whether the marked up-regulation of HIF-1 expression was due to systemic hypoxia, the inflammatory cascade, or both. Regardless of the proximal cause, up-regulation of HIF-1 expression, notably nuclear expression, could then promote the amplification of the cytokine cascade, contributing to the systemic inflammation response syndrome (SIRS). We have demonstrated that H5N1-infection in macaques induces profound and sustained up-regulation of mRNA for IFNs and their downstream signaling molecules, as well as for IL-1, IL-6 and TNF-α, accompanied by very significant levels of circulating IL-6 and TNF-α proteins [23] . Furthermore, pronounced nuclear and cytoplasmic expression of HIF-1α was demonstrated by IHC in peripheral blood leukocytes and tissue macrophages (described in this paper), and phospho-p38α-MAPK expression was up-regulated in both the respiratory tract and lymphoid tissues, lending support to the contention that increased cytokinemia is indeed induced during H5N1 infection, with systemic effects as a consequence. This interpretation is corroborated by findings by Lee et al. [3, 41] , who also demonstrated that high cytokine levels in peripheral blood correlated with increased phospho-p38α-MAPK expression in H5N1 infection in human patients.