geted approach to the clinic. Foremost among them is the need to examine the potential risk that immunization against conserved viral features could under some circumstances result in immunopathology (e.g., immune enhancement) rather than protection (Epstein, 2004). The cost of these measures—particularly RNAi, which would be classified as a drug therapy—is also prohibitively expensive as currently delivered.
Given that the next influenza pandemic is widely expected to be avian in origin and to emerge from domestic poultry (though perhaps detouring through pigs or another mammalian species on the way), it would seem desirable to inhibit the replication of influenza viruses in chickens, greatly reducing the danger of transmission to humans or other livestock. Recent developments in transgenic technologies and inhibitory strategies make possible the engineering of disease-resistant livestock, including influenza A-resistant chickens; meanwhile, research on the influenza virus has revealed promising strategies for inhibiting influenza replication (see Tiley and Sang in Chapter 5). In addition to RNAi, described above, influenza A replication potentially could be suppressed through the introduction of Mx genes—which block the expression of incoming viral genomes in several mammal and bird species, but not in chickens—and through the presence of RNA decoys, short sequences that mimic the binding sites of RNA proteins and thereby act as competitive inhibitors for transcription. By combining these strategies, researchers hope to achieve complete blockage of influenza replications and prevent the development of resistant viral strains; if they fall short of this goal, dangerous “silent epidemics” of sub-clinical infection could occur (see the earlier discussion of this phenomenon in relation to avian influenza vaccines).
Until recently, the lack of a delivery system suitable for engineering the chicken genome posed a major roadblock to developing influenza virus-resistant poultry. Thanks to the advent of lentiviral vectors, which can be prepared to very high concentrations and can successfully infect and integrate into the chromosomes of virtually any cell type, the first attempts to produce influenza-resistant transgenic birds are currently underway. If these efforts prove successful, researchers must then face the far more daunting challenge of demonstrating the system’s long-term efficacy, and perhaps more importantly, its lack of detrimental effects on chickens, humans who consume poultry products, and the environment. While acknowledging that many people hold negative attitudes toward genetically modified organisms, presenter Laurence Tiley (see Chapter 5) observed that “even the direst GMO scare-mongering scenario” pales in comparison to that of another 1918.