Avian flu resisting antiviral drugs, says CU study
By Jim Scott
The avian flu, an Influenza A subtype dubbed H5N1, is evolving a resistance to a group of antiviral drugs known as adamantanes, one of two classes of antiviral drugs used to prevent and treat flu symptoms, said CU-Boulder doctoral student Andrew Hill, lead study author. The rise of resistance to adamantanes -- which include the nonprescription drugs amantadine and rimantadane -- appears to be linked to Chinese farmers adding the drugs to chicken feed as a flu preventative, according to a 2008 paper by researchers from China Agricultural University, said Hill.
In contrast, resistance of the avian flu virus to the second, newer class of antiviral drugs that includes oseltamivir -- a prescription drug marketed under the brand name Tamiflu -- is present, but is not yet prevalent or under positive genetic selection, said Hill of CU-Boulder's ecology and evolutionary biology department. The CU findings should help health administrators around the world plan for the possibility of an avian flu pandemic.
The CU-Boulder study is the first to show H5N1 drug resistance to adamantanes arose through novel genetic mutations rather than an exchange of RNA segments within cells, a process known as re-assortment, said Hill. The research on the mutations, combined with molecular evolution tests and a geographic visualization technique using Google Earth, "provides a framework for analysis of globally distributed data to monitor the evolution of drug resistance," said Hill.
The CU-Boulder-led study appears online in the journal Infection, Genetics and Evolution. Co-authors included CU-Boulder Associate Professor Robert Guralnick, recent CU-Boulder graduate Meredith Wilson, Farhat Habib of Kansas State University and Daniel Janies of Ohio State University.
"As these adamantanes have gotten into nonhuman vectors like birds, the positive selection for resistance to avian flu is rising," said Hill. "If Tamiflu is ever used in the manner of adamantanes, we could conceivably see a similar resistance developing through positive selection."
The research team used an interactive "supermap" using Google Earth technology that portrays the individual gene mutations and spread of the avian flu around the globe, said Guralnick of CU-Boulder's ecology and evolutionary biology department. By projecting genetic and geographic information onto the interactive globe, users can "fly" around the planet to see where resistant H5N1 strains are occurring, said Guralnick, also Hill's doctoral adviser.
For the study, the researchers analyzed 676 whole genomes of Influenza A/H5N1 from National Institutes of Health databases of viruses isolated between 1996 and 2007. The team is comparing how often amino acid sequence changes in genes lead to mutations that affect drug resistance in the H5N1 virus and how often such changes evolve into random mutations that don't affect resistance, Hill said.
The next step is to analyze 2008 data, he said.
First detected in China in 1996, the avian flu has spread throughout Asia and to India, Russia, Pakistan, the Middle East, Africa and Europe by various carriers, including poultry and migratory waterfowl, Hill said. While H5N1 is not highly communicable to humans from birds or between humans, experts are concerned future evolution of this subtype or other subtypes, or genetic re-assortment between subtypes, could make an avian influenza strain more contagious with the potential to cause a pandemic.
Like the legend of a road map, colors and symbols on the supermap indicate which types of hosts carry the virus or the distribution of genotypes of interest, said Hill. A click by users on viral "isolates" generates computer windows revealing H5N1 mutations linked to positive genetic selection resulting from the spread and use of adamantanes.
For still images and a KMZ file of the Google Earth project, visit the Web at biodiversity.colorado.edu/.
Jim Scott is senior science editor for the CU Office of News Services.
The avian flu, an Influenza A subtype dubbed H5N1, is evolving a resistance to a group of antiviral drugs known as adamantanes, one of two classes of antiviral drugs used to prevent and treat flu symptoms, said CU-Boulder doctoral student Andrew Hill, lead study author. The rise of resistance to adamantanes -- which include the nonprescription drugs amantadine and rimantadane -- appears to be linked to Chinese farmers adding the drugs to chicken feed as a flu preventative, according to a 2008 paper by researchers from China Agricultural University, said Hill.
In contrast, resistance of the avian flu virus to the second, newer class of antiviral drugs that includes oseltamivir -- a prescription drug marketed under the brand name Tamiflu -- is present, but is not yet prevalent or under positive genetic selection, said Hill of CU-Boulder's ecology and evolutionary biology department. The CU findings should help health administrators around the world plan for the possibility of an avian flu pandemic.
A new University of Colorado at Boulder study shows the resistance of the avian flu virus to a major class of antiviral drugs is increasing through positive evolutionary selection, with researchers documenting the trend in more than 30 percent of the samples tested.
The CU-Boulder study is the first to show H5N1 drug resistance to adamantanes arose through novel genetic mutations rather than an exchange of RNA segments within cells, a process known as re-assortment, said Hill. The research on the mutations, combined with molecular evolution tests and a geographic visualization technique using Google Earth, "provides a framework for analysis of globally distributed data to monitor the evolution of drug resistance," said Hill.
The CU-Boulder-led study appears online in the journal Infection, Genetics and Evolution. Co-authors included CU-Boulder Associate Professor Robert Guralnick, recent CU-Boulder graduate Meredith Wilson, Farhat Habib of Kansas State University and Daniel Janies of Ohio State University.
"As these adamantanes have gotten into nonhuman vectors like birds, the positive selection for resistance to avian flu is rising," said Hill. "If Tamiflu is ever used in the manner of adamantanes, we could conceivably see a similar resistance developing through positive selection."
The research team used an interactive "supermap" using Google Earth technology that portrays the individual gene mutations and spread of the avian flu around the globe, said Guralnick of CU-Boulder's ecology and evolutionary biology department. By projecting genetic and geographic information onto the interactive globe, users can "fly" around the planet to see where resistant H5N1 strains are occurring, said Guralnick, also Hill's doctoral adviser.
For the study, the researchers analyzed 676 whole genomes of Influenza A/H5N1 from National Institutes of Health databases of viruses isolated between 1996 and 2007. The team is comparing how often amino acid sequence changes in genes lead to mutations that affect drug resistance in the H5N1 virus and how often such changes evolve into random mutations that don't affect resistance, Hill said.
The next step is to analyze 2008 data, he said.
First detected in China in 1996, the avian flu has spread throughout Asia and to India, Russia, Pakistan, the Middle East, Africa and Europe by various carriers, including poultry and migratory waterfowl, Hill said. While H5N1 is not highly communicable to humans from birds or between humans, experts are concerned future evolution of this subtype or other subtypes, or genetic re-assortment between subtypes, could make an avian influenza strain more contagious with the potential to cause a pandemic.
Like the legend of a road map, colors and symbols on the supermap indicate which types of hosts carry the virus or the distribution of genotypes of interest, said Hill. A click by users on viral "isolates" generates computer windows revealing H5N1 mutations linked to positive genetic selection resulting from the spread and use of adamantanes.
For still images and a KMZ file of the Google Earth project, visit the Web at biodiversity.colorado.edu/.
Jim Scott is senior science editor for the CU Office of News Services.
A longer version of this story originally appeared on the news center site
Jan. 7, 2009