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Novel HA Cleavage Site in Romania H5N1 Bird Flu
Recombinomics Commentary
October 22, 2006

The sequence of H5N1 isolated from a chicken in Romania last year, A/chicken/Romania/4793/05(H5N1), has been released.  The partial HA sequence has a novel HA cleavage site, GDRRKKR.  This is the first public sequence of H5N1 from Romania, which reported one of the first confirmed H5N1 cases in the region in October, 2005.  Although the sequences generated by Weybridge have been withheld, a phylogenetic tree of HA H5N1 sequences in Europe has been published.  There are several distinct groupings on the tree that include isolates from Romania.  However, the full presentation included a discussion of the isolates from Europe describe several novel cleavage sites, but no contained the E to D change seen above, suggesting that the published sequence represents yet another version of the Qinghai strain of H5n1 circulating in Europe.

The cleavage sit above has not been reported previously, but the E to D change has been found in geese in Malaysia.  That cleavage site is generated by taking the common HA cleavage site in H5n1 in Asia, RERRRKKR and changing the E to generate RDRRRKKR.  Similarly, the common Qinghai change has changed he first position of the common sequence to a G, resulting in GERRRKKR.  Thus, the novel cleavage site in Romania can be generated by recombining the Malaysian duck sequence with the common Qinghai sequence.

The partial HA sequence has additional polymorphisms shared by a subset of the Qinghai isolates.  A1099G is shared with Qinghai isolates from the area, but the polymorphism is also found in many H5N1 isolates from Indonesia.  The sharing of polymorphsism between a subset of Qinghai isolates and a subset of Indonesian isolates signal additional recombination between these two groups.

Recent sequences from China define the evolution of H5N1, including isolates from 1997, with the 20 amino acid NA deletion found in the Z Genotype, which exploded out of China in 2004.  These sequences have many clear-cut examples of recombination, and can also be found in wild birds.  These isolates also share regions of identity with Indonesian isolates, including human isolates from the Karo cluster as well as the Indonesia sub-clade chosen as a vaccine target.

Recently, WHO expanded the number of H5N1 vaccine targets to four, because of four distinct clades or sub-clades linked to fatal infections in humans.  These expanded targets highlight the rapid evolution of H5N1 due to extensive recombination in a population of increased genetic complexity.  The sharing of polymorphisms between these distinct groups helps define additional recombination events that define future vaccine targets.

The HA sequence released today from a patient infected this month has additional examples of regions of H5N1 shared between Qinghai and Indonesian isolates.

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