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H5N1 Acquisitions of Mammalian Polymorphisms Cause Concern
Recombinomics Commentary
November 15, 2006

New H5N1 sequences released this month provide additional examples of recombination, including the acquisition of mammalian polymorphisms.  H5N1 PB2 sequences from southern China had several examples, which extended regions of identity between H5N1 sequences and human H3N2 and H1N1 sequences.  As these regions of identity grow, the potential for additional acquisitions also grow, because the new acquisitions increase the size of the region of identity.  In addition, as the avian gene becomes more "mammalian-like", additional acquisitions are more compatable with the evolving genome.  Thus, the acquisition rate can accelerate as the mammalian polymorphisms accumulate.

These mammalian  acquisitions have been described previously for H5N1 human isolates in Vietnam and Thailand in 2004.  As the database of public sequences grow, additional examples are identified which has also been found in the PB2 gene of recently released Fujian PB2 sequences (see examples of growing regions of identity here)

H5N1 changes in the receptor binding domain have attracted interest because H5N1 has already infected humans and is associated with a high case fatality rate.  The speficity of the receptor binding is dictated by a relatively small number of amino acid positions, so changes in these positions can dramatoically change the binding of the H5N1, without affecting the assocaite case fatality rate.  Recently, S227N was found in Qinghai isolates from patients in Turkey and Egypt.  The S227N chnaged had been previously shown to increase the affinity for 2,6 gal receptors, found in teh upper respiratory tract of humans, and lower affinity for 2,3 gal receptors found in the gut of birds.  In the Qinghai strain, this acquisition is of concern, because Qinghai isolates have already fixed another mammalian polymorphism, PB2 E627K.

The recently released H5N1 sequences contain many examples of changes in the HA cleavage site as well as the receptor binding domain.  The poly-basic HA cleavage site can be cleaved by a variety of tissue specific protease, so changes in that region can affect tissue tropism.  Each dominant strain causing human cases has distinct HA cleavage represent Clade 1, and the three Clade 2 sub-clades being used as targets for H5N1 pandemic vaccines.

Recent isolates also have a number of changes in the receptor binding domain.  There have been several recent examples from China that have multiple changes in the receptor binding domain, including another chnage at position 227, S227R..  As has been seen previously for the HA cleavage site, various combinations of receptor binding domain changes have been seen in the receptor binding domain.

One change that has caused concern is M230I, which was found in the H5N1 from a recent fatal case in Egypt.  M230I is a mammalian polymorphism.  It is the dominant amino acid in the two circulating influenza A serotypes, H3N2 and H1N1 as well as influenza B.  Although this change has been found in a limited number of prior H5N1 isolates, it is the first example of the change in the Qinghai strain.  The change is also present in a limited number of other serotypes, including  important mammalian isolates such as H3N8 in dogs and horses, H7N7 in seals, horses, and humans, as well as H7N3 in humans.

More information on changes in the receptor binding domain will be detailed in a subsequent commentary.

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