7 Animal models for the study of drug-resistant influenza virus infections The potential for influenza viruses to develop resistance to amantadine and rimantadine has been well established in clinical studies (Monto and Arden, 1992, Hayden and Hay, 1992, Englund et al., 1998) and in mice (Sidwell et al., 2003). By contrast, viruses that have acquired resistance to zanamivir and oseltamivir generally display a significant reduction in infectivity in mice, compared to the parent viruses (Gubareva et al., 2000, Herlocher et al., 2004, Yen et al., 2005). This reduction in virulence has been evaluated by several means. In one study, mice were infected in parallel with equal quantities of the parental and the mutant viruses, and lungs were removed early in the infection (Gubareva et al., 1997). The virus titer in each was then determined and the titers of the challenge viruses needed to induce a 50% infection were compared or the amount of virus produced in the lungs by equivalent concentrations of the viruses was quantified (Tai et al., 1998). Alternatively, using a mouse-adapted influenza virus, the relative virulence of the mutant virus was assessed using parameters such as increased lung weight, lung pathogenesis scores, lung histopathology, and decreased SaO2% levels of the lungs (Sidwell et al., 1995). Ferrets have been used extensively to study the infectivity and virulence of influenza virus mutants resistant to the neuraminidase inhibitors (Blick et al., 1998, Gubareva et al., 1998b, Barnett et al., 2000). Blick et al. (1998) found that a zanamivir-resistant influenza virus with an NA and HA mutation was not resistant to zanamivir in ferrets, even though a small decrease in sensitivity to the drug had been shown in mice, indicating some potential differences in the two models when studying drug-resistant viruses. A summary of current animal models available for studying drug-resistant influenza virus infections is presented in Table 8 . Table 8 Summary of current animal models available for studying drug-resistant influenza virus infections. Virus Animal Model Drug References Influenza A H4N2 Mouse (BALB/CBYJ) Neuraminidase inhibitors Gubareva et al. (1997) A/turkey/Minnesota/833/80 Influenza A H1N1 Mouse (C57BL6 X C57BL10) Ferret Zanamivir Blick et al. (1998) NWS/G70C4-G