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H7N9 E627K Raises Pandemic Concerns
Recombinomics Commentary 09:30
April 8, 2013

The release of full sets of sequences by The Harbin Veterinary Institute has allowed for comparisons with the four human sequences.  Although these sequences are closely related, the PB2 E627K in all human sequences was absent from all three avian sequence.

The earliest human sequence, A/Shanghai/1/2013, was the most diverse, and did not have H7 Q226L a key receptor binding domain.  Q226L was in the next two human sequences, A/Shanghai/2/2013 and A/Anhui/1/2013.  This position evolved further to L226I in A/Hangzhou/1/2013, signaling human adaptation.
The three avian H7N0 sequences   from a pigeon, (A/Pigeon/Shanghai/S1069/2013), chicken (A/Chicken/Shanghai/S1053/2013), and environment (A/Environment/Shanghai/S1088/2013) are from recent samples.  They were congenic  with the human sequences and did not have E627K. 

This difference is significant, since E627K produces temperature dependent differences in polymerase activity.  Avian sequences typically have an E at position 627 which produces optimal activity at 40 C, the body temperature of a bird, while E627K produces optimal activity at 33 C

Prior to the H7N9 outbreak there have been only one reported death due to bird flu, which was a veterinarian infected with H7N7 during the 2003 outbreak in the Netherlands, which had E627K.  Thus, the presence of E627K in the first three cases, which were severe or fatal, and the expectation of E627K in the most recent human sequence, which was also from a fatal case, raises serious pandemic concerns.

Key markers identified in H5N1 transmission experiments.  The abolishment of the glycosylation of position 158, was already present, while the more recent human cases also had H7 Q226L and all had PB2 E627K.

Moreover, all sequences have D225G and M230I.  D225G is in all H5N1 sequences and was also linked to severe H1N1pdm09 cases, as well as a subset of 1918 cases.  M230I is present in human seasonal flu (H3N2 and influenza B) raising additional transmission concerns.
Thus, the presence of E627K in all human H7N9 reported to date, and its absent in the avian sequences, significantly increases pandemic concerns.

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