Tamiflu Resistance Increases Pandemic Concerns
Recombinomics Commentary 22:48
March 24, 2008
"They all say if you get resistance in seasonal flu it will be useless when the pandemic comes along," Laver says. "That's just nonsense," because a global outbreak would be caused by a new flu strain.
Laver's research helped scientists create molecules that block neuraminidase, one of the two surface proteins on influenza viruses that let the pathogen spread from infected cells to other cells in the body. This eventually led to development of Tamiflu and GlaxoSmithKline's inhaled treatment, Relenza.
The above comments on Tamiflu resistance and pandemic implications fail to understand the role of recombination in influenza evolution. The sudden appearance of Tamiflu resistance and high frequencies in countries like Norway are not easily explained by the random mutation dogma of influenza genetics.
Circumstantial data strongly suggest that the H274Y in H1N1 seasonal flu is linked to H5N1 resistance linked to prophylactic treatment. H274Y was first reported in northern Vietnam in early 2005. These examples were followed by the report of H274Y in Qinghai H5N1 in wild birds in Europe. The H5N1 in Astrakhan was closely related to H5N1 in Denmark and Sweden, defining a transmission route from southeast Asia to Scandinavia.
These long range linkages as well as polymorphism jumps, from humans to birds and vice verse, are cause for concern. The current best candidate for the next pandemic is H5N1. There have been 237 confirmed bird flu fatalities in humans. 236 of these fatalities have been linked to H5N1. The only other confirmed fatality was due to H7N7 in the outbreak in the Netherlands in 2003.
The N1 in H5N1 is an unusually poor target for Tamiflu. The likelihood of the development of resistance is increased through prophylactic doses used in Tamiflu blankets. This combination could explain the appearance of an evolutionarily fit resistant H5N1 in swan isolates in Astrakhan.
Consequently, the growing frequency of H274Y in H1N1 seasonal flu could lead to additional resistance in H5N1 because of recombination between N1 from H1N1 and N1 from H5N1.
Influenza geneticists have actively ignored the role of recombination in influenza genetic drift. The increase in the number of sequences has made distribution pathways more obvious and reduced the role of random mutations in influenza evolution. The cross over of polymorphism from birds to humans, possibly through swine intermediates is creating added genetic diversity, which can be accelerated by the ability of H5N1 to infect multiple mammalian species.
Although H274Y highlights such exchanges, the exchanges via recombination are common and becoming more frequent, leading to the creation of multiple H5N1 targets, and an increasing rate of evolution in seasonal flu.
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