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Qinghai H5N1 Receptor Binding Domain Changes In Middle East
Recombinomics Commentary
November 19, 2006

Moreover, two of these changes, lysine at position 182 and arginine at position 192, were present in the HAs of clade-2 H5N1 viruses isolated from two individuals in Azerbaijan and one individual in Iraq, but not in any of the more than 600 avian isolates examined.

The above comments indicate that two of the changes that increase receptor binding are found in additional human H5N1 Qinghai isolates in the Middle East,  The changes  above, which correspond to positions 186 and196 in the H3 numbering, are in addition to S227N and M230I, which have also been detected in Qinghai isolates in Turkey and/or Egypt.

Previously, attention had been focused on positions 226 and 228 which had become Q226S and G228L in human H3N2.  However, Q226 and G228 were in initial H2N2 human isolates in 1957 at the beginning of that pandemic, and Q226 and G228 are in current influenza B, and they are in virtually all influenza B sequences, which include isolates from 1940 through 2006.  Moreover, the recent H5N1 from Egypt has M230I, which is in all three current serotypes, H3N2, H1N1 and influenza B.  M230I in influenza B creates a five amino acid stretch of identity between H5N1 and influenza B (QSGRI).  Moreover, influenza B has N186K, which as indicated above is also in Qinghai isolates in Azerbaijan and Iraq.

Although the Azerbaijan and Iraq sequences described above are being hoarded in the WHO database, and are not public, the only public human H5N1 sequence from Iraq also has a change at position 186 except the change is from N to S (N186S).  This change is also found in the initial H3N2 isolates associated with the beginning of the 1968 pandemic.  Moreover, it is also H3N8 sequences from dogs and horses.  The dog H3N8 is easily transmitted from dog to dog, highlighting its presence in additional mammalian species.  It has also been found in a recently released 1997 H5N1 isolate from Hubei, A/chicken/Hubei/wi/1997.

The presence of Q196R in the Middle East is also a concern, because it synergizes with S227N, which has been detected in human H5N1 in Turkey and Egypt.  Thus, in addition to the mammalian polymorphisms, PB2 E627K, the Qinghai isolates in the region have N186K, N186S, Q196R, S227N, and M230I.  These polymorphisms are either linked to increases in affinity for human receptors, or have been found in human isolates, suggesting various combinations can lead to more efficient human to humans transmission.  Since all are on the Qinghai strain, recombination between these sequences, can be expected, as has been seen previous in H5N1 HA cleavage site as well as the receptor binding domain.

These co-circulating polymorphisms in Qinghai isolates in the Middle East. create additional concerns.

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