Using a macaque model of influenza [22, 23] and employing a recent human isolate of H5N1 influenza A virus as well as reassortant H1N1 influenza A viruses containing genes encoding two (HA, NA) or four (HA, NA, NS1 + NEP) proteins of the 1918 Spanish influenza virus strain, we previously reported on pulmonary pathology [23] . We subsequently have sought to further address questions regarding extrapulmonary virus replication and inflammationassociated extrapulmonary effects caused directly or indirectly by these virulent viruses. In particular, we hypothesized that the transcription factor hypoxia inducible factor-1 (HIF-1) would be up-regulated in animals with severe pneumonia, either as a result of hypoxia or the inflammatory response. HIF-1 has emerged as a key regulatory molecule due to its responsiveness to both microenvironmental tissue conditions, such as hypoxia, and inflammatory mediators [24] [25] [26] [27] [28] . We found that the expression of HIF-1α appeared to reflect the extent and kinetics of lung inflammation following infection with these influenza viruses and was an indicator of extrapulmonary tissue reactions in the absence of frank pathology or virus replication.