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Fixing of Human Polymorphisms in H5N1 in Wild Birds

Recombinomics Commentary

January 13, 2006

Genetic and antigenic analyses have shown that, compared to previous H5N1 isolates, 2004–2005 isolates share several amino acid changes that modulate antigenicity and perhaps other biological functions. Furthermore, our molecular analysis of the HA from isolates collected in 2005 suggests that several amino acids located near the receptor-binding site are undergoing change, some of which may affect antigenicity or transmissibility. For example, an isolate (VN/JP12-2/05) showed a change from serine to asparagine at position 223 of the HA1 (S223N) that may affect receptor-binding specificity.

The above comments from a WHO report in Emerging and Infectious Diseases adds some additional information regarding the S227N (also called S223N) poymorphism found in an isolate from a fatal Turkish case, but specifics are lacking.  The WHO report on the Manila meeting  in May, 2005 mentioned changes in positions near the receptor binding domain for northern Vietnam isolates, but did not give details.  The data in the  table associated with the above comments indicates the S227N in Vietnam was only found in human isolates.

This species restriction monitors another change, PB2 E627K, which was also limited to mammalian isolates prior to Qinghai Lake in May, 2005.  In Vietnam, Thailand, and Hong Kong, this change was only found in mammalian isolates and was associated with poor outcomes.  However, it was detected in all 16 wild bird isolates from Qinghai Lake and appears to be fixed in the migratory bird population, because all subsequent isolates have had the change.  This change is of concern because it allows H5N1 to grow efficiently at 34 C, the temperature of a human nose in the winter.

The large number of cases and clusters in Turkey suggest S227N has also become fixed in the bird population, although the wording in the WHO announcement is somewhat unclear on the number of changes found in the receptor binding domain.  The description indicates one change is S227N, but no details are given for additional changes.

The composition of the 2005 isolates from Vietnam are also unclear, because none of the sequences have been made public, even though the above isolate was described in a peer reviewed journal, which usually requires sequences be made pubic.

The acquisition of S227N was predicted based on donor sequences present in H9N2 in the Middle East.  The presence of H5N1 in migratory birds allowed for dual infections involving H5N1 and H9N2 in the Middle East, which may have been due to the expected recombination.  The fixing of S227N in the bird population is cause for concern.

The two isolates from the Hong Kong patients in 2003 did not have the PB2 E627K, so the human isolate from Turkey may be the first example of H5N1 with both HA S227N and PB2 E627K. 

Moreover, both changes may now be fixed in H5N1 in birds, which moves H5N1 on step closer toward sustained human-to-human transmission.


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