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H5N1 Acquisition Matches Influenza B Receptor Binding Domain
Recombinomics Commentary
November 15, 2006

The H5N1 HA sequence of the recent fatal infection in Egypt was  released within days after confirmation.  The acquisition of the mammalian polymorphism, M230I, produced a match with the sequence adjacent to the human receptor binding domain of influenza A (H3N2 and H1N1) and influenza B.  The change creates identity between positions 226-230 (QSGRI) in the receptor binding domain of influenza B. 

Moreover, the change produces identity in positions 223-230 (VNGQSGRI) as well as 190(E) in H7N7.  This receptor binding domain sequence was present in the only fatal avian influenza case in the 2003 H7N7 outbreak in the Netherlands.  H7N7 antibodies were present in hundreds of contacts of cullers, indicating the H7N7 was readily transmitted from human-to-human.  The same receptor binding domain was present a human isolate from the H7N3 outbreak in British Columbia, as well a 1980 H7N7 seal sequence.  The sequence matches canine H3N8 at positions 225-230 GQSGRI.  Canine H3N8 is also easily transmitted from dog to dog.

These matches raise questions about the WHO monitoring of positions 226 and 228, which are L and S in human H3N2 and H1N1.  In 1957, pandemic H2N2 had Q and G at positions 226 and 228 providing additional evidence that such sequences allow for efficient influenza transmission in humans. 

This potential is also support by recent data indicating the levels of H5N1 in the throat of patients in Vietnam were higher than seasonal flu.  These data raise serious questions about the requirement for changes at positions 226 and 228 which are closely monitored by the WHO and consultant.  The recent PNAS paper on the spread of the Fujian strain in China noted that "The receptor-binding pocket of HA1 retains amino acid residues Gln-222 and Gly-224(H5 numbering used throughout) that preferentially bind to 2,3-NeuAcGal linkages of avian cell-surface receptors (12, 13)."  These two positions correspond to 226 and 228 in the H3 number system used above, and human H3 isolates have Leu and Ser at these positions.  Thus, WHO and consultants are monitoring changes at these two positions, even though human influenza B as well as 1957 pandemic H2N2 have the "avian" Q and G at that position, as does H5N1 and mammalian serotypes H3N8 (in canine and equine) and H7N7 (in seal and equine),

Thus, the acquisition of mammalian M230I in the patient in Egypt creates a human Qinghai H5N1 with a poly-basic HA cleavage site, as well as a receptor binding domain with additional identity with human influenza, and a human PB2 E627K polymorphism, which increases polymerase activity at lower temperatures.

These data raise questions about the rationale for monitoring changes in positions 226 and 228 and raise concerns that additional acquisitions  via recombination with an increasing diverse H5N1 genome in wild bird populations, will generate a pandemic H5N1 that is efficiently transmitted human to human that is coupled to an alarmingly high case fatality rate.

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