Re: J Clin Microbiol. Oseltamivir-Resistant Influenza A Viruses Circulating in Japan.
I think it is time for a review. The paper on this thread is part of a large scale effort directed at the emergence (and fixing) of H274Y in H1N1. Discussions and a refocus began over a year ago when Norway announced that 2/3 of the H1N1 patients that they tested were Tamiflu resistant, which was markedly higher than prior seasons, when resistance was rarely detected in H1N1 or H3N2. However, there had been prior spikes in cases in Japan, where Tamiflu use was widespread, and sub-optimal dosing was used on younger patients. In that outbreak, resistance was in H1N1 and H3N2 and involved multiple positions in each serotype.
In Norway however, the situation was quite different. The patients infected with Tamiflu resistant influenza were not taking Tamiflu. Moreover, all cases of resistance were in H1N1 and all involved one position, H274Y. It soon became clear that the resistance was widespread and almost all cases were in patients not taking Tamiflu. Moreover, all of the resistance was in H1N1 and at position H274Y.
It soon became clear that the above description of events had actually begun several seasons earlier, but at a lower level. H274Y was in clade 2C of H1N1 in isolates from patients in China, who also had not taken Tamiflu. Initial cases were from 2006. That was followed by cases in the 2006/2007 season in the United States and England, which involved clade 1. In the following season (2007/2008) cases were identified prior to the reported cases in Norway. The earlier cases were in the United States and Australia, but involved clade 2B. Shortly thereafter, one strain of the clade 2B sub-clade began to emerge. It was in Norway as well as many other countries including multiple locations in the US. All of these isolates were collected in late 2007, but additional examples were found in early 2008.
These results led to an unprecedented release of sequence data on H1N1. Most of these early sequences were released by the US CDC and placed on deposit at Genbank. This was followed by sequences from many countries, including those in Europe, which quickly produced a large database of H1N1 isolates from the 2007/2008 season. In addition to these sequences at Genbank, other angencies deposited additional sequences at databases such as GISAID, which required registration, but the sequences were public. Similarly, many of the state agencies published phylogentic trees, which provided additional information on the relationship between the various isolates, along with H274Y status and collection dates.
It soon became clear that the H274Y levels were due to multiple independent introductions. Most introductions involved limited spread, but some involved isolates from multiple countries in multiple continents.
However, most isolates were linked to the dominant strain that emerged at multiple locations worldwide in late 2007. This strain led to the dominant strain in South Africa in mid-2008, although less common strains in South Africa linked back to independent earlier introductions in the northern hemisphere.
The strain that was dominant in the southern hemisphere in mid-2008 gave rise to the clade 2B H1N1 that had H274Y levels close to 100% and these high levels have become fixed in most countries in the northern hemisphere.
Thus, H274Y was really at hitch-hiker that jumped from one genetic background to another. Earlier, the jumping moved from one sub-clade to another (clade 2C to clade 1 to clade 2B). Introductions into clade 2B led to the most productive expansions, including the strain that became dominant in 2007/2008 that led to various versions of that strain, which have H274Y because of hitch-hiking events in 2007. The strain that emerged acquired a series of additional changes in HA and NA, which traced back to clade 2C isolates. One change, HA A193T, was in a subset of the strain that dominated in 2007/2008 in the northern hemisphere, as well as the dominant strain in the southern hemisphere in 2008, and is in all reported H274Y positive clade 2B isolates reported to date, including a large number of isolates at Genbank and GISAID.
I think it is time for a review. The paper on this thread is part of a large scale effort directed at the emergence (and fixing) of H274Y in H1N1. Discussions and a refocus began over a year ago when Norway announced that 2/3 of the H1N1 patients that they tested were Tamiflu resistant, which was markedly higher than prior seasons, when resistance was rarely detected in H1N1 or H3N2. However, there had been prior spikes in cases in Japan, where Tamiflu use was widespread, and sub-optimal dosing was used on younger patients. In that outbreak, resistance was in H1N1 and H3N2 and involved multiple positions in each serotype.
In Norway however, the situation was quite different. The patients infected with Tamiflu resistant influenza were not taking Tamiflu. Moreover, all cases of resistance were in H1N1 and all involved one position, H274Y. It soon became clear that the resistance was widespread and almost all cases were in patients not taking Tamiflu. Moreover, all of the resistance was in H1N1 and at position H274Y.
It soon became clear that the above description of events had actually begun several seasons earlier, but at a lower level. H274Y was in clade 2C of H1N1 in isolates from patients in China, who also had not taken Tamiflu. Initial cases were from 2006. That was followed by cases in the 2006/2007 season in the United States and England, which involved clade 1. In the following season (2007/2008) cases were identified prior to the reported cases in Norway. The earlier cases were in the United States and Australia, but involved clade 2B. Shortly thereafter, one strain of the clade 2B sub-clade began to emerge. It was in Norway as well as many other countries including multiple locations in the US. All of these isolates were collected in late 2007, but additional examples were found in early 2008.
These results led to an unprecedented release of sequence data on H1N1. Most of these early sequences were released by the US CDC and placed on deposit at Genbank. This was followed by sequences from many countries, including those in Europe, which quickly produced a large database of H1N1 isolates from the 2007/2008 season. In addition to these sequences at Genbank, other angencies deposited additional sequences at databases such as GISAID, which required registration, but the sequences were public. Similarly, many of the state agencies published phylogentic trees, which provided additional information on the relationship between the various isolates, along with H274Y status and collection dates.
It soon became clear that the H274Y levels were due to multiple independent introductions. Most introductions involved limited spread, but some involved isolates from multiple countries in multiple continents.
However, most isolates were linked to the dominant strain that emerged at multiple locations worldwide in late 2007. This strain led to the dominant strain in South Africa in mid-2008, although less common strains in South Africa linked back to independent earlier introductions in the northern hemisphere.
The strain that was dominant in the southern hemisphere in mid-2008 gave rise to the clade 2B H1N1 that had H274Y levels close to 100% and these high levels have become fixed in most countries in the northern hemisphere.
Thus, H274Y was really at hitch-hiker that jumped from one genetic background to another. Earlier, the jumping moved from one sub-clade to another (clade 2C to clade 1 to clade 2B). Introductions into clade 2B led to the most productive expansions, including the strain that became dominant in 2007/2008 that led to various versions of that strain, which have H274Y because of hitch-hiking events in 2007. The strain that emerged acquired a series of additional changes in HA and NA, which traced back to clade 2C isolates. One change, HA A193T, was in a subset of the strain that dominated in 2007/2008 in the northern hemisphere, as well as the dominant strain in the southern hemisphere in 2008, and is in all reported H274Y positive clade 2B isolates reported to date, including a large number of isolates at Genbank and GISAID.
