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Shangxi H5N1 Has Multiple Receptor Binding Domain Changes
Recombinomics Commentary
November 9, 2006

The complete sequence of all eight gene segments from a chicken isolate from northern China, A/chicken/Shangxi/2/2006(H5N1).  The release of this sequence may be linked to the comments in lass week's PNAS paper regarding the spread of the Fujian strain of H5N1 in southern China.  Researchers from Harbin noted that H5N1 in northern China was quite distance from the southern China isolates, and the above sequence, from the Harbin labs, is quite distance, but is a recombinant with regions of identity with a sequence from northern China, A/chicken/Hebei/326/2005 as well as sequences from southern China, A/chicken/Hunan/2246/2006(H5N1) and A/chicken/Hunan/2292/2006(H5N1).

The new isolate has a novel HA cleavage site, REGRRKKR, which was previously found in a 1997 isolate in Hebei  (A/chicken/Hebei/wk/1997(H5N1) and more recently in a number of Hunan isolates reported in the PNAS paper last week as well as tree sparrow sequences from Henan.  This sequence probably recombined with the Qinghai cleavage site, GERRRKKR, to generate the cleavage site found in Qinghai isolates in the Sudan, GEGRRKKR.  The recent Hebei isolate above, also has a related cleavage site, REGGRKKR which is related to two Hunan isolates, REGGRRKR.

However, the isolate from Shangxi had a number of changes in and around the receptor binding domain.  The Shangxi sequence had two changes, R220K and K222Q, near the four changes in the Shantou isolates, (V214M, K222R, V223I, S227R) and has four changes flanking the 190 position (A188E, A189T, T192I, L194I).  The two related sequences from Hunan also have two of the four changes downstream from 190 (T192I and L194L), but also has two changes upstream, D187N and A189E.  Thus, there are five polymorphisms flanking 190 at positions 187, 188, 189, 192, 194 as well as upstream changes at 214, 222, 223, 227 including three versions of 189 and 227.  This large number of co-circulating changes in or near the receptor binding domain offers and increasing large number of combinations generated via recombination, which is also happening in the HA cleavage site.

These small changes that have led to the request of The WHO for hundreds or thousands of sequences from northern China, because although these changes may not produce large changes, they are at critical regions of H5 where single amino acid changes can have dramatic effects on the ease of human to human transmission as well as the tissue tropism and lethality of the many versions of H5N1 co-circulating in China.

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