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Selection Against Altered Receptor Binding in  H5N1 in Indonesia

Recombinomics Commentary

June 9, 2006

CA Nidom in a recent interview indicated he has collected 100 samples from poultry, swine, and people in the Jakarta area.  He detected 20 isolates, presumably H5N1 bird flu, and 11 had alpha 2.6 specificity.  This finding was alarming because alpha 2.6 linkages are found in the human upper respiratory tract and that specificity would make H5N1 transmission more efficient.

WHO updates however, have indicated that there were no “significant mutations’ that affect receptor binding.  This discrepancy with the Nidom result may be due to a narrow definition of “significant” by WHO.  It is generally assumed that the two “significant" positions in the receptor binding domain are 226 and 228.  However, a change between those two positions S227N is also linked to an increased affinity for alpha 2.6 linkages.

This specificity was found in two isolates from Hong Kong, A/Hong Kong/212/2003(H5N1) and A/Hong Kong./213/2003(H5N1).  More recently that change was predicted via acquisition of sequences from H9N2 in the Middle East by the Qinghai strain of H5N1.  That change was found in the index case in Turkey who was part of the largest H5N1 cluster to date, as described in the recent New York Times article by Donald McNeil.  However, media reports indicate S227N was not found in H5N1 from the sister of the index case.

The failure to find S227N in the Turkish sibling may have been related to isolation procedures.  Since alpha 2.6 has a preference for mammalian receptor, growth in chicken eggs could select against that change.  The Hong Kong isolates were grown in a mammalian cell line, MDCK, which is a dog kidney line, and S227N was isolated from both related samples (from a father and son)..

Thus, if Hong Kong and the CDC are growing human H5N1 on chicken cells prior to sequencing, the sequence may reflect the changes during cultivation, which may select against mammalian receptor binding specificities such as S227N (or chnages at positions 226 and/or 228).

If alpha 2,6 specificity, coupled with PB2 E627K are co-circulating widely in the Jakarta area, then increased human-to-human transmission would be expected, which may also be linked to the novel cleavage site found in human isolates in the Jakarta area.

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