Together, these data imply that in the complex environment of the luminal surface of the human ciliated airway epithelium, the viral surface antigens have a marked effect on the extent of virus infection and that temperature plays an important role in limiting avian, but not human, influenza virus infection and spread in the cooler proximal airway regions. Given these results, we draw attention to other recently published data using the HAE model in which mutations in viruses that are growth attenuated in vivo display similar growth attenuation in HAE but not in nondifferentiated cell lines, suggesting that HAE possess discriminating properties of attenuating phenotypes of mutants of respiratory viruses [26, 27] . Admittedly, in the present study, despite restriction in both growth and spread, wild-type avian viruses and human viruses with avian or avian-like glycoproteins did eventually reach high titer at 32uC at later time points. The efficiency of infection and replication of a virus that inoculates the airway epithelium, however, is likely a critical factor in determining whether the virus is capable of establishing infection in a host that normally possesses innate and adaptive immune systems that attempt to limit virus infection and spread. At temperatures of the distal airways, avian influenza viruses displayed similar infection kinetics as human influenza viruses and would therefore, in the case of sufficient inoculum reaching these distal regions, be as likely to establish infection. Indeed, the clinical pathology findings for humans infected with H5N1 do report distal airway infection in ciliated bronchioles and lung regions [22] . Under these conditions of inoculation and infection, avian influenza viruses present in the distal airways may still be unable to spread to proximal airway regions without additional adaptation to cooler temperatures. One caveat of this prediction is that virus may be transported to proximal airway regions by innate mucus clearance mechanisms indicating that caution is required when attempting to identify proximal infection by viruses in airway secretions obtained from tracheal swabs.