study:Avian influenza viruses increase drug resistance in Asia
submited by kickingbird at Sep, 11, 2005 13:53 PM from Xinhua News Agency
By sequencing the virus gene for M2 protein, which is closely linked with virus?ability to replicate, researchers at the St. Jude Children´s Research Hospital found proportion of drug-resistant H5 and H9 avian influenza virus subtypes is rising in Asia.
In a paper published in the online issue of the journal Virology, the researchers said that treating chickens with amantadine, a widely used antiviral drug, will put selective pressure on the M2 gene to acquire mutations that made virus drug-resistant.
H5 influenza viruses concern health officials because H5N1 subtype has been spreading throughout chicken flocks and wild birds in Asia since it emerged in 1997. Highly pathogenic avian H5N1 influenza has infected more than 100 people, and killed millions of birds in some Asian countries.
"Humans don磘 have resistance to H5N1, and currently vaccines to H5N1 are still being developed. And, the available evidence shows that the most recent strains isolated from humans in Asia are no longer sensitive to inhibition by the amantadine family of drugs," said Robert Webster, senior author of the study.
Resistance to the antiviral drug amantadine is caused by substitutions of one of five amino acids in the part of the M2 protein called the transmembrane domain -- the part of M2 located within the coat of the influenza virus.
The M2 protein is an ion channel located in the envelope of thevirus that permits hydrogen ions (protons) to enter the flu virion. This influx of protons allows the virus to shed its coat after it enters a cell -- an essential step in the replication of the virus. Amantadine inhibits the function of the M2 protein and thus stops viral replication.
By analyzing the sequence of the transmembrane part of the M2 gene, the researchers were able to determine how frequently amantadine resistance occurs in avian influenza A subtypes isolated in various parts of the world.
They study the M2 gene sequences from 60 flu viruses isolated in Southeast Asia and 74 from North America that represented the H5, H6, H7 and H9 subtypes, and examined information on 408 viruses isolated from avian hosts worldwide.
From 1979-83, there were no avian amantadine-resistant strains isolated in the northeastern US and Southeast Asia, but in 2000-2004, 31 percent of H5 and 11 percent of H9 influenza virusesfrom Asia isolated carried M2 mutations, the team found.
Although the specific amantadine-resistance mutations in M2 canoccur randomly throughout the world, these mutations in Asia are undergoing strong selective pressure, the researchers said.
The increasing incidence of amantadine-resistant H5N1 viruses in Asia indicates that these variants appear to have survival advantages over the wild, drug-sensitive strains.
In addition, the infected birds die so rapidly there is no timefor the virus to acquire a large number of mutations, among which could be changes in the M2 protein.
Therefore, the high rate of M2 mutations in Asia probably arises from some human activity that encourages selection of such changes, the researchers said.
For example, treating chickens with amantadine to prevent infection with H5N1 would put selective pressure on the gene to acquire mutations that made it resistant to this drug.
"Any selective pressure on this virus ensures plenty of opportunity for H5N1 to acquire amantadine resistance, which would bring additional difficulties in controlling the pandemic," Webster noted.
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