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Between Indonesia and Egypt
The sequences in Indonesia evolved from a 2006 sub-clade represented by (A/Chicken/West Java/SMI-CSLK-EC/2006, A/chicken/West Java/SMI-CSLK-EB/2006, A/Chicken/West Java/PWT-WIJ/2006, A/Chicken/West Java/SMI-PAT/2006, A/chicken/Jakarta/DKI-Nurs/2007). The more recent sequences acquired a number of changes including a 3 BP deletion (S133del) as well as a non-synonymous change C500T (I151T).
However, both of these acquisitions, as well as a synonymous change, C321T, which was in the earlier sequences from the West Java sub-clade, were appended onto an Egyptian clade 2.2.1 genetic background to create clade 2.2.1.G, which was first reported in Egypt in early 2007 and has become the dominant sub-clade in Egypt. This sub-clade became prominent in human cases in early 2009 where almost all cases in Egypt were in toddlers. These cases were mild and only 4 of the 39 H5N1 confirmed cases in Egypt died (in contrast to the 40% case fatality rate in Egypt before and after the 2009 series). Moreover, since mid-2009, all reported human H5N1 sequences in Egypt have been clade 2.2.1 G.
These new sequences add to the compelling data supporting influenza evolution via recombination, which places the same polymorphisms on multiple genetic backgrounds. This rapid evolution has significance with regard to transmitting H5N1. Rubin Donis from the US CDC published a paper on modifications of a clade 2.2 isolate from Egypt, which included three changes two receptor binding domain changes on HA (Q226L and G228S) as well as PB2 E627K. Ron Fouchier from the Erasmus Medical Centre in the Netherlands placed the same three changes on a clade 2.1 isolate from Indonesia and passaged the construct in ferrets 10 times to select for two additional changes, on of which was likely Q196R, which was also used by the CDC team. Thus, the same set of changes on two different H5N1 backgrounds was linked to efficient transmission in a ferret model.
Although the two receptor binding domain changes at positions 226 and 228 have not been identified in natural H5N1, changes at positions 223 (V223I) and 230 (M230I) were found in a clade 2.2 fatal cluster in Egypt, and these two changes subsequently became fixed on clade 2.3.2 isolates in wild birds and a recent fatal human case in Shenzhen.