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H5N1 M230I Migration in East Asia
Recombinomics Commentary 14:37
May 20, 2008

The presence of M230I in the two HA sequences from whooper swans in Japan help define a migration pathway connecting Japan to Hong Kong.  M230I has attracted attention because it is one of two receptor binding domain changes in the Gharbiya cluster, which is the largest confirmed cluster to date in Egypt.  M230I was also found in additional cases in the 2006/2007 season in Egypt and all cases with M230I were fatal.  Moreover, M230I is present in all three strains of seasonal flu (H3N2, H1N1, influenza B) raising concerns of H5N1 adaptation in humans.

All reported H5N1 isolates west of China have been clade 2.2.  The first report of M230I in clade 2.2 was from an eagle owl in Germany in 2006.  The first reports of M230I in Egypt were at the beginning of the 2006/2007 season and found in human and avian isolates.  The sequences from the Egyptian cases this season have not been released, but avian sequences from this season have M230I and V223I, the other receptor binding domain change in the Gharbiya cluster.

However, prior to the reports of M230I in clade 2.2, there were reports of sequences from Vietnam with M230I.  These sequences were a sub-clade of the Fujian strain, clade 2.3.2.  Clade 2.3.2 was also reported in at least one wild bird isolate from Hong Kong in 2007, which was selected as the vaccine target for clade 2.3.2.  This sequence has not been released. However, phylogenetic analysis indicates that the sequence will be closely related to the two sequences from Japan, strongly suggesting that the sequence will also have M230I.

In the clade 2.2 isolates, M230I was appended onto different genetic backgrounds in Germany and Egypt.  The more recent Egyptian isolates evolved from the isolates from the prior season.  Similarly, M230I has been appended onto clade 2.1 genetic backgrounds in Indonesia, including a swine isolate.  However, the sequences from Vietnam, Hong Kong, and Japan all map onto the same branch of the clade 2.3.2 phylogenetic tree, indicating the full gene migrated from Vietnam to Hong Kong to northern Japan.  Thus, the tracing of M230I in this series defines movement via a migration route, just as routes of migration were defined by the spread of clade 2.2 through Europe, the Middle East, and Africa.  These sequences define H5N1 migration that goes through intersecting distribution routes in Japan and South Korea.  South Korea has also indicated clade 2.3.2 has been detected in the largest H5N1 outbreak reported to date in South Korea.

However, isolates from Japan which have a clade 2.3.2 HA sequence also have clade 2.3.4 sequences in the other gene segments.  In NA these sequences are closely related to a human NA sequence from Guangdong, A/human/China/GD02/2006, as well as wild bird sequences from Hong Kong.  Thus, the isolates in Japan are reassortants with clade 2.3.2 and 2.3.4 sequences. The presence of these reassortants in whooper swans migrating out of Japan and South Korea raise concerns that these Fujian sequences will spread to regions in Mongolia and Siberia where clade 2.2 sequences have been reported, as well as into North America via Alaska and the Aleutian Islands.

Thus, the tracing of M230I helps define a migration route that connects various countries in eastern Asia, from Indonesia to Japan.  The clade 2.3.2 and 2.3.4 sequences define a subset within the East Asia flyway which connects Vietnam, Hong Kong, Japan, and South Korea which raises concerns that such sequences will significantly spread along these routes to expand the H5N1 geographic reach and genetic diversity.

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