Seasonal H1N1, Shows Signs of Resisting Tamiflu
If the behavior of how seasonal flu virus H1N1 is any indication, the scientists say chances are good that most strains of H1N1 influenza pandemic will be resistant to Tamiflu, the main drug storage to be used against them.
Researchers at Ohio State University have traced the evolutionary history of seasonal influenza virus H1N1, which first infected humans during the 1918 pandemic. It is one of three seasonal influenza viruses that usually infect humans. The others are H1N2 and H3N2.
In H1N1, two strains of virus circulating in humans: a seasonal basis, and the shape of an influenza pandemic known as swine flu, which has sickened millions and killed thousands of people since it was first time in North America last spring.
Over time, the H1N1 strain of seasonal flu survivors throughout the world has developed mutations that have caused them to become resistant to oseltamivir based on agents. Tamiflu is the brand name of oseltamivir phosphate.
“Something happened in 2008, when it seized drug resistance,” said Daniel Janies, an associate professor of biomedical informatics at Ohio State and lead author of the study. “The drug-resistant isolates became of the survivors worldwide. This is just static now. The season of influenza virus H1N1 has been set in resistance.”
Janies and his colleagues have traced the history of the same mutation in the H1N1 strain of the pandemic virus and the contact details of his appearance last spring until December 2009. And they’re starting to see the same type of mutation in the virus – an amino acid changes that allow the virus to resist the effects of oseltamivir – as seen in the H1N1 flu season.
“It’s a pretty good bet that whatever the pressure is on the environment, overuse of Tamiflu or something else driving the seasonal flu and become resistant to Tamiflu will also apply to an influenza pandemic,” said Janies. “We can see that happening already.
“This has the potential to indicate that we will have to think of anything else to use for the treatment of H1N1 influenza pandemic.”
The same study showed that resistance to an antiviral drug second – zanamivir, known by the trade name Relenza – not as frequent, suggesting this drug might be a good alternative to Tamiflu, he said.
The research appears online in the International Journal of Health Geographics.
Until now, most strains of H1N1 pandemic that have been isolated from humans are susceptible to Tamiflu. From 3 February 2010, 225 cases of pandemic H1N1 virus was reported to be resistant to the drug provided the millions of cases of disease with swine flu in the United States and elsewhere.
But resistant cases, and how mutations have resulted in Tamiflu resistance in H1N1 seasonal offers clues about how the virus transforms to survive against the popular drug.
The two H1N1 viruses, seasonal and pandemic influenza are similar on the surface, where the proteins interact with cells in the human body. But the genes of the virus internally configured differently.
The researchers focused on specific points of the neuraminidase protein – this protein is what the “N” refers to these names virus subtype. The oseltamivir resistance in H1N1 can develop as a result of a mutation in one of several locations of this protein, Janies said.
He and his colleagues analyzed the mutations in the neuraminidase protein of 1210 seasonal H1N1 viruses isolated worldwide between September 2004 and December 2009. The pandemic of the H1N1 virus, researchers examined mutations at specific points in the neuraminidase protein of the virus in 1824 collected between March 2009 and December 2009.
“With the rapid availability of sequence data from the public about pandemic flu, we can see evolution in essence, in real time,” said Janies.
Once selected strains of the study, researchers used powerful supercomputers to analyze the evolution of these proteins and their different mutations. The computing power that allows them to match similar regions in proteins and make the data in the context of mutation over time and geography.
One result of these calculations is called a phylogenetic tree, which documents the history of mutations – including those that cause drug resistance. Phylogeny is the study of evolutionary relationships and characteristics among various biological species, genes or proteins that share a common ancestor.
In tracing the history of the neuraminidase of the H1N1 pandemic and seasonal, the group found that mutations in the same position of amino acids in seasonal and pandemic influenza H1N1 virus led to resistance to antivirals.
“Basically, a change in the amino acid changes like the folds of the neuraminidase protein, and the Tamiflu molecule has the ability to interfere with the virus,” said Janies.
The researchers also used a technique that compared different types of mutations – those that cause resistance to antiviral and other do not have this – to see what type of mutation is more common.
“We see the relationship between mutations that confer resistance to those who do not, and if the ratio is greater than 1 means that the change is driven by natural selection rather than chance. Something is driving the evolution of drug resistance “Janies said. “We could see that happening in seasonal influenza and the data we have so far for a flu pandemic, too.
“A Darwinist would say that something changed that made the Tamiflu resistant strain more appropriate than the wild type,” he said.
The group also examined the mutations that alter these two strains of H1N1 virus responses to Relenza. The resistance to this drug is relatively rare, Janies said, which could be attributed to less frequent use of the drug or the possibility that the mutations leading to resistance to Relenza are not tolerated by the virus itself, so that strains die.
Janies noted that there is another phenomenon with most influenza pandemic strains could make it difficult to treat. In at least 50 geographic regions identified by analysis, both seasonal and pandemic H1N1 viruses are co-movement, including strains resistant to Tamiflu. Because influenza viruses in general, is not accurate when it makes copies of itself, this means that a drug-susceptible strain of pandemic could change in a gene with a viral strain resistant and add it to the new genome.
“And then we would have drug-resistant influenza pandemic without any mutation. This is a random exchange of entire gene,” said Janies of this phenomenon, called redistribution.
“That’s how we got into this situation with pandemic flu. We have something called H1N1 pandemic virus, but all their internal genes are different. He suffered a series of rounds of redistribution and it is a virus we’ve never seen before, because its genome is highly remodeled compared to seasonal H1N1. This same process could confer resistance to one drug, “he said.
Researchers have mapped the areas where the pandemic flu and seasonal influenza drug resistant circular with Google Earth using software called AquaMaps. Regions in the United States and Japan are among those in which an influenza pandemic isolates carrying the mutation of Tamiflu resistance. The regions of co-movement can be seen in http://pointmap.osu.edu.
The power calculation used in this study was provided by the Ohio Supercomputer Center and Ohio State University Medical Center. This work is funded by the U.S. Army Research Laboratory and the Office.
Janies co-authored the study with Igor Voronkin, Jonathon Studer, Jori Hardman, Boyan Alexandrov, Travis Treseder and Chandni Valson, all from Ohio State Department of Biomedical Informatics.
Tags: amino acid, around the world, data, drug, drug resistance, drug-resistant, flu, h1n1, h1n1 influenza, h1n1 influenza virus, h1n1 viruses, history, humans, influenza, influenza virus, janies, mutation, mutations, neuraminidase, ohio, ohio state, pandemic, pandemic h1n1, pandemic influenza, protein, proteins, regions, researchers, resistance, resistant, resistant to tamiflu, seasonal, seasonal and pandemic, seasonal h1n1, seasonal h1n1 influenza, seasonal influenza, something, state, strain, strains, tamiflu, virus, viruses, world