**Acknowledgements**

differences between species in the PB2, NP, M and NS-containing segments. These differences were only on the positive strand which could indicate a role in either protein production or negative strand synthesis. Given that these segments do not reassort as frequently as the other polymerase segments or glycoprotein segments, it would seem that genome wide RNA structural organization does not contribute to reassortment. Al‐ though, it is postulated that global organizational RNA structure could be a mechanism by which the virus adapts to the host environment [101] leaving open the possibility that the RNA structure of a particular segment affects the chances of it being involved in

228 Current Issues in Molecular Virology - Viral Genetics and Biotechnological Applications

DI particles represent an evolutionary dead end with regard to a natural infection. However, particles that lack a complete genome could be either detrimental or beneficial in vaccine production. Particles that are defective in the polymerase will alter growth characteristics and would not function in a live attenuated vaccine. In contrast, particles with incomplete genomes represent an abundance of antigen with no pathogenicity, which could be viewed as desirable

Understanding the gene constellation effect in influenza is important, especially for vaccine production. The mixing and matching of influenza genomic segments in nature and in the laboratory gives rise to new viruses with phenotypes that differ from the ancestral viruses. In nature, this may be a more pathogenic virus or one that has an expanded host range. In the laboratory, attenuated viruses with good growth characteristics and high protein yield are desirable for study and vaccine production. A greater understanding of what contributes to the gene constellation effect may enable researchers to produce influenza vaccine seed viruses

As we have described in this chapter, current research has provided some insight into the genomic features that contribute to the gene constellation effect, but more work needs to be done. Some segments, such as those encoding the glycoproteins and the polymerase proteins, appear to be more frequently involved in reassortments. The reassortment of the polymerase proteins is more common in laboratory manipulation whereas the reassort‐ ment of glycoproteins is more common in nature. The beneficial effects of certain pro‐ tein:protein interactions may be the underlying impetus behind some of these reassortments. For example, certain combinations of HA, NA and M can lead to changes in transmission and growth. Likewise, certain combinations of PB1, PB2 and PA can affect polymerase activity and growth. Also, the two smallest segments have effects on cell tropism and viral fitness. The amount of polymerase activity is not directly associated with virus titer suggesting other factors affecting replication must be balanced with replication efficiency. Changes in the polymerase segments can also affect pathogenicity, especially when the virus is adapting to a new host cell. Changes in the glycoproteins have also been shoen to affect pathogenicity. While much work has focused on either the glycoproteins

that facilitate production with reduced risk of infection.

reassortment.

in an inactivated vaccine.

**4. Conclusion**

The findings and conclusions in this chapter have not been formally disseminated by the Food and Drug Administration and should not be construed to represent an Agency determination or policy.
