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From Recombinomics.
Quote
Silent Spread of E627K in Pandemic H1N1 Patients
Recombinomics Commentary 14:01
September 29, 2009
Sequence analysis of 12/24 clinical specimen available at the institute identified 10 A(H1N1)v viruses that clustered with the virus obtained from the diabetic index patient based on unique mutations in the NA gene and PB2 gene. Only one of these had the PB2 E627K mutation. This virus was isolated from a family contact of an adolescent girl who returned from a one-week stay on the same island on Mon 20 Jul 2009 with high fever and coughing.
The above description from a ProMed report on isolates in the Netherland raise concerns that virus with E627K is silently transmitting. This polymorphism was found in two of thirteen similar sequences, which do not appear to be linked. The index case for the detection is not directly linked to the sibling described above. It is unclear if the adolescent girl described above had E627K. The failure to detect may have been due to a lack of a sample or the failure to isolate a virus or sequences with E627K from that patient.
However, it is unlikely that the two positive samples are due to independent spontaneous “mutations”. It is much more likely that the E627K is in a mixture, and isolation procedures or sequencing approaches lead to frequent detection of the avian version of PB2, which has an E at PB2 position 627. The only prior report of E627K in a pandemic H1N1 sequence was from a patient in Shaghai. The original sequence, as well as the first sub-clone had E627K, while a second sub-clone had E627.
This type of mixture could not only allow for the spread of E627K, but could also lead to elevated levels in the upper respiratory tract, due to the dominance of E627K, followed by increased levels of H1N1 in the lower respiratory tract due to a dominance of E627. The silent spread of E627K could be linked to the increased severity of pandemic H1N1 infections being reported at schools throughout the northern hemisphere.
Like NA H274Y, the mixture produces sequences that are dependent on selection pressure. H274Y has been most commonly detected in patients receiving oseltamivir, although at least two isolates were from patients not receiving oseltamivir, and the presence of H274Y in the second camper in North Carolina is probably not linked to oseltamivir use, since it has the same rare genetic marker found in the index case. Similarly, the shared markers in the Netherland isolates with E627K argue for transmission, but the two positives are not directly linked and most samples tested do not have detected E627K.
These data highlight the need for more aggressive cloning and sequencing. The acquistion of NA H274Y was predicted because if a high frequency in seasonal H1N1, while PB E627K is at high frequency in PB2 in seasonal H1N1 and H3N2. Recombinations allows for the jump of both polymorphsism from a seasonal flu background to pandemic H1N1.
The presence of mixtures at PB2 position 627 could have catastrophic consequences, linked to site specific increases in viral load. Similarly, release of sequences would allow for a fuller understanding of the dsitribution of the sub-clade isolated in the Netherlands with and without E627K.
Immediate release of these sequences wold be useful.
Recombinomics Commentary 14:01
September 29, 2009
Sequence analysis of 12/24 clinical specimen available at the institute identified 10 A(H1N1)v viruses that clustered with the virus obtained from the diabetic index patient based on unique mutations in the NA gene and PB2 gene. Only one of these had the PB2 E627K mutation. This virus was isolated from a family contact of an adolescent girl who returned from a one-week stay on the same island on Mon 20 Jul 2009 with high fever and coughing.
The above description from a ProMed report on isolates in the Netherland raise concerns that virus with E627K is silently transmitting. This polymorphism was found in two of thirteen similar sequences, which do not appear to be linked. The index case for the detection is not directly linked to the sibling described above. It is unclear if the adolescent girl described above had E627K. The failure to detect may have been due to a lack of a sample or the failure to isolate a virus or sequences with E627K from that patient.
However, it is unlikely that the two positive samples are due to independent spontaneous “mutations”. It is much more likely that the E627K is in a mixture, and isolation procedures or sequencing approaches lead to frequent detection of the avian version of PB2, which has an E at PB2 position 627. The only prior report of E627K in a pandemic H1N1 sequence was from a patient in Shaghai. The original sequence, as well as the first sub-clone had E627K, while a second sub-clone had E627.
This type of mixture could not only allow for the spread of E627K, but could also lead to elevated levels in the upper respiratory tract, due to the dominance of E627K, followed by increased levels of H1N1 in the lower respiratory tract due to a dominance of E627. The silent spread of E627K could be linked to the increased severity of pandemic H1N1 infections being reported at schools throughout the northern hemisphere.
Like NA H274Y, the mixture produces sequences that are dependent on selection pressure. H274Y has been most commonly detected in patients receiving oseltamivir, although at least two isolates were from patients not receiving oseltamivir, and the presence of H274Y in the second camper in North Carolina is probably not linked to oseltamivir use, since it has the same rare genetic marker found in the index case. Similarly, the shared markers in the Netherland isolates with E627K argue for transmission, but the two positives are not directly linked and most samples tested do not have detected E627K.
These data highlight the need for more aggressive cloning and sequencing. The acquistion of NA H274Y was predicted because if a high frequency in seasonal H1N1, while PB E627K is at high frequency in PB2 in seasonal H1N1 and H3N2. Recombinations allows for the jump of both polymorphsism from a seasonal flu background to pandemic H1N1.
The presence of mixtures at PB2 position 627 could have catastrophic consequences, linked to site specific increases in viral load. Similarly, release of sequences would allow for a fuller understanding of the dsitribution of the sub-clade isolated in the Netherlands with and without E627K.
Immediate release of these sequences wold be useful.
Source: http://www.recombinomics.com/News/09290902/H1N1_E627K_SS.html 
