Identification of Step in Flu Virus Replication Supports Development of New Vaccines

Influenza viruses continue to pose a severe threat worldwide. The major difficulty in defending against influenza virus infection is the high genetic variability of the virus. The rapid generation of reassortant viruses means they can escape the immunity acquired against previous virus strains, or become resistant to antiviral agents.

During infection, the interaction of the virus with the host supports the virus life cycle and pathogenesis. The virus activates cellular signalling pathways and hijacks the host’s cellular machinery to enable viral replication and propagation. These key cellular events – essential for efficient virus replication and propagation – might be the target for anti-influenza interventions.

This team’s research focuses on these interactions between the influenza virus and the host. Specifically, by genetically changing influenza viruses via reverse genetics technology, the team has been studying how viral genes and gene products activate cellular signalling pathways in the host and how the pathways support virus propagation and pathogenesis.

It is known that the influenza A virus infection activates a specific pathway in the host (PI3K/Akt), but it is not known how. The entire process can be thought of as an assembly line (the PI3K/Akt pathway) with a switch to turn it on or off. This study reports that a specific protein of the influenza A virus, the NS1 protein, acts as the “switch” responsible for pathway activation. There is a lock-and-key structure whereby the NS1 protein fits a factor in the pathway, thus activating the process. The team found the specific area of the pathway with which the NS1 protein interacted (called the p85 regulatory subunit of PI3K) and the exact site of its binding.

This information allowed the team to create viruses with mutations in the NS1 protein, and the team confirmed that these viruses were unable to activate the PI3K/Akt pathway, and in turn, the virus was severely limited in its ability to reproduce itself.

This finding is significant for several reasons. First of all, influenza viruses for use in vaccines are generally grown in poultry eggs, but avian influenza viruses can kill the embryo. This technology weakens the virus so that avian influenza viruses could effectively be grown in eggs.

Secondly, vaccines work best – that is, they create the strongest and most protective immune responses – when the antigen is a live but weakened version of the disease-causing organism. Since the team now knows how to create influenza viruses with mutations in the NS1 protein, this technology could be applied to the development of live vaccines against influenza.

This knowledge about how the influenza virus interacts with the host could also support the development of drugs to prevent the binding of the NS1 protein to its binding site in the host, thus severely restricting the virus’s ability to launch an infection.

The researchers point out that additional research is needed to reveal the exact influence of the PI3K/Akt pathway on the propagation of the influenza virus, and the pathway’s role in other aspects of infection. However, the researchers have shed light on how this key pathway is activated, as well as contributing new knowledge about the role of the NS1 protein.

Shin, Y-K; Liu, Q; Tikoo, S.K.; Babiuk, L.A. and Y. Zhou. Journal of General Virolology 2006 ,DOI 10.1099/vir.0.82419-0. Published online 21 October 2006

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