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Tamiflu resistance in pandemic influenza - historical compilation of news
Tamiflu resistance puzzle
Category: Antivirals ? Influenza treatment ? Swine flu
Posted on: July 23, 2009 7:00 AM, by revere
There have been three reported oseltamivir (Tamiflu) resistant isolates of H1N1 swine flu (added: and now a fourth in Canada) but with those exceptions all others have been sensitive to this oral antiviral. This is in marked contrast to the other H1N1 strain, the seasonal variety which is almost entirely resistant. The spread of Tamiflu resistance in the seasonal strain happened with dramatic suddenness in the winter of 2007 - 2008 and came as an unhappy surprise. People assume that a rapidly mutating virus would inevitably become resistant, but based on several laboratory studies there were reasons to believe the mutation or mutations conferring resistance also made the virus less fit to replicate, infect host cells or cause disease. Moreover the resistance developed and spread very rapidly in areas where the virus was under little antiviral pressure. But the resultant H1N1 seasonal viruses transmitted readily and caused a typical influenza illness. It was a public health problem, but also in interesting scientific one. Now a clue may be emerging in findings just published in a Letter in Emerging Infectious Diseases from scientists in Luxembourg.
Several mutations in the neuraminidase (NA) gene can cause Tamiflu to lose its effectiveness at blocking the virus's ability to detach its replicated progeny after infecting a host cell (and thus preventing further infection of other cells), but by far the most common is one designated H274Y. The 274 part is the amino acid location along the protein, while the H and Y say that Y has been substituted for H at that location. H is an abbreviation for the amino acid histidine, while Y is the abbreviation for tyrosine. In other words, in a resistant H1N1 virus, there is a change at a single place along the long string of amino acid beads that make up the N1 protein and it occurs 274 places down the line, substituting a tyrosine from a histidine building block. That's a pretty small change but it's enough to interfere with the docking of the Tamiflu to the neuriminidase enzyme on the virus's surface and allow it to perform its detaching function. But is this change all that's involved? Apparently not.
NA is not the only protein made by the virus. Also on its surface is hemagglutinin (HA, one version of which, H1, gives H1N1 part of its name), which is involved in viral attachment to the host cell (and other functions) and 6 other gene segments, most internal to the virus and involved in replication and other functions. Could it be that the virus with mutant NA had other less visible mutations that somehow "mde up for" or corrected the lack of fitness found in resistant viruses with only H274Y? The scientists in Luxembourg compared sequences in all 8 gene segments in Tamiflu resistant versus sensitive H1N1s to see if there was another consistent change. They looked at 140 different isolates collected by Luxembourg's National Influenza Sentinel Surveillance System over the period when resistance emerged (December 2007 - March 2008). About a quarter of these isolates were Tamiflu resistant. They then searched for another genetic marker that accompanied H274Y but wasn't in H274 (the sensitive virus). No difference in most of the other genes -- PB1, polymerase A, hemagglutinin, nucleoprotein, matrix, nonstructural (NS) -- seemed to differentiate resistant from non-resistant. The exception was the PB2 gene, where a serine for proline change at position 453 (Pro453Ser) seemed to fit the bill. They looked at all published PB2 sequences to see if this was a common mutation and were able to find only three instances collected since 1918: one each in 1933, 1976 and 1988.
The bottom line here is that these two genetic changes -- H274Y in NA and Pro453Ser -- are associated and seem to be related to the unexpected fitness of Tamiflu resistant seasonal H1N1.
Science is a slow process and fitting all the pieces together takes even more time. There are false starts and backtracks and sometimes things that seem significant are only side tracks or misinterpretations. Whether this finding is indeed true, and if true, how it works mechanistically we don't know. But it's a clue that might tell us something important about viral fitness and Tamiflu resistance. Could it affect the pandemic? Possibly, if the existence of Pro453Ser could be used as a marker or early warning of developing Tamiflu resistance. Another possibility, that it might provide information about a new therapeutic target, is probably too distant to have any application in the next year or two.
Science marches to its own rhythm.
Tamiflu resistance puzzle
Category: Antivirals ? Influenza treatment ? Swine flu
Posted on: July 23, 2009 7:00 AM, by revere
There have been three reported oseltamivir (Tamiflu) resistant isolates of H1N1 swine flu (added: and now a fourth in Canada) but with those exceptions all others have been sensitive to this oral antiviral. This is in marked contrast to the other H1N1 strain, the seasonal variety which is almost entirely resistant. The spread of Tamiflu resistance in the seasonal strain happened with dramatic suddenness in the winter of 2007 - 2008 and came as an unhappy surprise. People assume that a rapidly mutating virus would inevitably become resistant, but based on several laboratory studies there were reasons to believe the mutation or mutations conferring resistance also made the virus less fit to replicate, infect host cells or cause disease. Moreover the resistance developed and spread very rapidly in areas where the virus was under little antiviral pressure. But the resultant H1N1 seasonal viruses transmitted readily and caused a typical influenza illness. It was a public health problem, but also in interesting scientific one. Now a clue may be emerging in findings just published in a Letter in Emerging Infectious Diseases from scientists in Luxembourg.
Several mutations in the neuraminidase (NA) gene can cause Tamiflu to lose its effectiveness at blocking the virus's ability to detach its replicated progeny after infecting a host cell (and thus preventing further infection of other cells), but by far the most common is one designated H274Y. The 274 part is the amino acid location along the protein, while the H and Y say that Y has been substituted for H at that location. H is an abbreviation for the amino acid histidine, while Y is the abbreviation for tyrosine. In other words, in a resistant H1N1 virus, there is a change at a single place along the long string of amino acid beads that make up the N1 protein and it occurs 274 places down the line, substituting a tyrosine from a histidine building block. That's a pretty small change but it's enough to interfere with the docking of the Tamiflu to the neuriminidase enzyme on the virus's surface and allow it to perform its detaching function. But is this change all that's involved? Apparently not.
NA is not the only protein made by the virus. Also on its surface is hemagglutinin (HA, one version of which, H1, gives H1N1 part of its name), which is involved in viral attachment to the host cell (and other functions) and 6 other gene segments, most internal to the virus and involved in replication and other functions. Could it be that the virus with mutant NA had other less visible mutations that somehow "mde up for" or corrected the lack of fitness found in resistant viruses with only H274Y? The scientists in Luxembourg compared sequences in all 8 gene segments in Tamiflu resistant versus sensitive H1N1s to see if there was another consistent change. They looked at 140 different isolates collected by Luxembourg's National Influenza Sentinel Surveillance System over the period when resistance emerged (December 2007 - March 2008). About a quarter of these isolates were Tamiflu resistant. They then searched for another genetic marker that accompanied H274Y but wasn't in H274 (the sensitive virus). No difference in most of the other genes -- PB1, polymerase A, hemagglutinin, nucleoprotein, matrix, nonstructural (NS) -- seemed to differentiate resistant from non-resistant. The exception was the PB2 gene, where a serine for proline change at position 453 (Pro453Ser) seemed to fit the bill. They looked at all published PB2 sequences to see if this was a common mutation and were able to find only three instances collected since 1918: one each in 1933, 1976 and 1988.
The bottom line here is that these two genetic changes -- H274Y in NA and Pro453Ser -- are associated and seem to be related to the unexpected fitness of Tamiflu resistant seasonal H1N1.
Science is a slow process and fitting all the pieces together takes even more time. There are false starts and backtracks and sometimes things that seem significant are only side tracks or misinterpretations. Whether this finding is indeed true, and if true, how it works mechanistically we don't know. But it's a clue that might tell us something important about viral fitness and Tamiflu resistance. Could it affect the pandemic? Possibly, if the existence of Pro453Ser could be used as a marker or early warning of developing Tamiflu resistance. Another possibility, that it might provide information about a new therapeutic target, is probably too distant to have any application in the next year or two.
Science marches to its own rhythm.
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