Influenza caused by highly-pathogenic avian H5N1 virus has been one of the most important zoonotic viral infections of humans during the last decade [1–3], with human fatality rates more than 50 percent in some areas of 15 affected countries [4], where outbreaks continue. Influenza viruses belong to the family Orthomyxoviridae, of which the H5N1 type has a broad range of hosts [1,5]. Although H5N1 naturally infects poultry and wild birds, transmission occurs to mammalian species, including humans [6–9]. H5N1-infected humans often develop severe clinical respiratory and gastrointestinal symptoms and signs; in some cases, symptoms of the central nervous system (CNS) ensue [10–13]. Infection of the CNS by H5N1 may be severe, causing encephalopathy and other serious neurological complications and sequelae [14–16]. Recent reports found that mice experimentally infected with H5N1 virus developed encephalitic lesions during the acute phase, which was associated with a degree of neuronal degeneration and necrosis. Interestingly, CNS inflammation has not generally been observed in the chronic phase of infection, despite the detection of virus in such lesions [17]. Furthermore, Jang et al. (2009) reported protein aggregation mediated by the influenza virus within degenerated and necrotic neurons. These findings suggest the hypothesis that pathogenic influenza virus might induce a “hit and run mechanism”, in which virus infection triggers a cytokine storm resulting in acute CNS inflammation, with consequent chronic Parkinson-like disease, encephalitis lethargica, or other neurodegenerative diseases. Nevertheless, the exact pathologic mechanism(s) of H5N1-induced encephalopathy remains unclear.