Our most recent work with the reconstructed 1918 virus was done in collaboration with Yoshihiro Kawaoka. In these studies, we evaluated the host response to the reconstructed virus using a cynomolgus macaque infection model [35] . The 1918 virus replicated to high levels and spread rapidly throughout the respiratory tract of infected animals, causing severe damage and masses of infiltrating immune cells throughout the course of infection. Genomic analyses revealed that the 1918 virus triggered an aberrantly high and sustained expression of numerous genes involved in the innate immune response, including proinflammatory cytokines and chemokines. The early and sustained host response in macaques infected with the 1918 virus was similar to what we observed in mice, indicating that critical host responses that influence disease outcome may occur very early after infection. Interestingly, the 1918 virus also appeared to selectively attenuate the expression of specific innate immune response genes, including certain genes associated with the type 1 interferon response. We have not determined the mechanism for this attenuation, but it is possible that the viral NS1 gene may play a role in regulating this response. Although the details remain to be uncovered, the atypical innate immune response induced by the 1918 virus was insufficient for protection and may actually contribute to the lethality of the virus.