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Additional H5N1 Acquisitions of Human RBD Polymorphisms
Recombinomics Commentary
November 15, 2006

two of these changes, lysine at position 182 and arginine at position 192, were present in the HA's of clade-2 H5N1 viruses isolated from two individuals in Azerbaijan and one individual in Iraq,clade

The above comments from today's Nature paper describe patients infected with the Qinghai strain of H5N1.  The paper identified acquisitions in human H5N1 isolates that enhanced binding to human receptors, either individually or in combination. 

The above comment is somewhat ambiguous.  It is not clear if all three patients had both receptor bind domain (RBD) changes described above, or both changes were found among the three patients.  The statement cannot be independently confirmed, because the sequences from these patients are still being hoarded by WHO, and have not been made public.

The hoarding of the sequences by WHO, weakens their complaints about China not sharing samples or sequences, when WHO and consultants at St Jude, Hong Kong University, and Weybridge are hoarding thousands of H5N1 sequence collected this year, including human cases as indicated above.

The hoarding labs have failed to understand how these changes are acquired and continue to call them random mutations.  The changes at position 182, described above corresponds to position 186 in the H3 numbering system.  The change of asparagine to lysine, N186K, creates a match with position 186 in the human influenza B.  This match is not mentioned in the Nature paper. 

Moreover, the public sequences from the index case in Iraq, also has a change at this position. This change, N186S, is found in the 1986 human pandemic sequence from Hong Kong, which also points toward its role in binding to human receptors.  The S at position 186 is also found in H3N8 sequences from dogs and horse, again pointing toward a role in recognizing mammalian receptors.

These changes in Qinghai isolates are important, because another mammalian polymorphism, PB2 E627K, has become fixed in the Qinghai strain.  This change is found in all human flu isolates and the change creates higher polymerase activity at lower temperatures (34 C).
The Nature paper also found S227N one of the patients in Vietnam, and receptor binding by S227N was enhanced by Q196R.  S227N has also been found in two of the human isolates from Turkey, as well as one from Egypt, which are more examples of changes in the receptor binding domain in Qinghai isolates that have E627K.

Thus, the number of changes in the receptor binding domain, or regions adjacent to the receptor binding domain in the Qinghai strain of H5N1 continue to increase.  The recent fatal case in Egypt, had M230I, which creates a change that matches all three human strains currently in circulation, H3N2 and H1N1 serotypes in Influenza A, as well as Influenza B.

The co-circulation of N186K, Q196R, S227N, and M230I in Qinghai strains which also have PB2 E627K remains a cause for concern, as WHO continues to hoard H5N1 sequences and continues to isolate H5N1 in chicken eggs, selecting against H5N1 isolates with the acquisition of these mammalian polymorphisms (the second sequence submitted to Genbank from the patient in Thailand has lost N186K).

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