Since the first reports of virus transmission from poultry to humans in 1997, highly pathogenic avian influenza H5N1 virus has spread throughout much of Asia, Europe, the Middle East and Africa. Cases of H5N1 in domestic poultry and water birds have been reported in over 40 countries since 2003, with the death or preventative culling of more than 200 million chickens causing devastation amongst poultry industries, particularly in South-East Asia. During 2004, widespread outbreaks of H5N1 occurred throughout Asia, where the virus crossed the species barrier to infect humans. Since then there have been almost 500 confirmed human cases of H5N1 infection reported in 12 countries. Furthermore, the 60% human mortality rate of H5N1 is alarming when compared to the approximate ML324
mortality rate of seasonal influenza A. H5N1 remains a significant threat of becoming a pandemic human disease, a scenario tied closely to global outbreaks in poultry. Therefore, novel therapies to combat zoonotic viruses like H5N1 are urgently needed. While vaccines against H5N1 are available, the lack of strain-specific vaccines during early-stage outbreaks creates a demand for alternative therapies. Compounding this is the shortcomings of existing antivirals and their loss of utility due to the emerging viral resistance to classes of neuraminidase and M2 ion channel inhibitors. RNA interference, the natural cellular pathway in which dsRNA input sequence is used to degrade target mRNA, is the basis for many therapeutics currently being developed against major human diseases. The exquisite specificity of RNAi-mediated gene silencing,Gossypin coupled with a potential to silence virtually any gene, makes RNAi an attractive basis for therapeutic design. Current clinical trials of RNAi-based therapeutics include treatments against several viral diseases, such as respiratory syncytial virus and hepatitis B. However it is wellestablished that select RNAi molecules can trigger off-target proinflammatory and antiviral cytokines which in many cases cause unwanted side effects. This phenomenon, known as immunos timulatory RNAi, may derive from the evolution of RNAi as an antiviral defence mechanism, as observed in plants and Drosophila.