The developing hindbrain

Bird flu pandemic would require multi-drug approach

14 May 2008

NIMR scientists have characterised a change in the N1 component of H5N1 which makes it resistant to the anti-viral drug Tamiflu. The mutation was found in human cases of the disease and suggests that a single drug approach is likely to be ineffective in case of a bird flu pandemic in humans. The findings are published online in Nature.

The research looked at the structure of the flu neuraminidase (N1), which is responsible for releasing the virus from infected human cells thereby allowing the disease to spread. N1 is the target for both the two existing flu drugs, Tamiflu and Relenza.

Using a method called X-ray crystallography, the scientists looked at a mutation in the structure of N1 neuraminidase that has been observed in human cases of H5N1 and in seasonal flu. They found that when this mutation occurred, the virus became resistant to Tamiflu, while still remaining susceptible to Relenza.

Viruses have a high rate of mutation often adapting to the treatments devised to tackle them. It had previously been thought that this mutation in N1 made it less virulent, but recent research from the United States has shown that the mutation does not reduce how infectious the virus is nor reduce its growth rate.

The team led by Dr Steven Gamblin (pictured) also looked at samples from the seasonal flu H1N1 and found that samples showing this mutation were also resistant to Tamiflu. In Norway this winter 70% of seasonal flu patients carried a virus that had mutated in this way. While the proportions were lower in other European countries, including the UK, there is no telling how the seasonal virus will evolve next year.

What this research shows is that stockpiling any one drug to prepare for a potential H5N1 pandemic is unlikely to provide adequate cover. In order not to be outflanked by the virus, it will be necessary to have stocks of both existing drugs. There is also a huge imperative to develop further drugs that could help disable this protein on the virus surface. It is likely a future pandemic will need to be tackled using a three- or four-pronged approach, much as we tackle HIV today.

Original article

The research findings are published in full in:

Patrick J. Collins, Lesley F. Haire, Yi Pu Lin, Junfeng Liu, Rupert J. Russell, Philip A. Walker, John J. Skehel, Stephen R. Martin, Alan J. Hay and Steven J. Gamblin. (2008)

Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants 

Nature, epub ahead of print. Abstract

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