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H5N1 S227N in Egyptian Patient
Recombinomics Commentary
November 7, 2006

HA sequences from 8 human H5N1 isolates from Egypt were released today by the US Naval Medical Research Unit 3 in Cairo (see list here).  These sequences were from the H5N1 outbreak in the spring.  Previously, one human sequence from a mild case in the spring, as well as a fatal case who died this month have been released.  The recent case has a change, M230I, near the receptor binding domain.

Changes in the receptor binding domain are of concern because of potential changes in binding to receptors on the surface of cells, which could affect transmission.  One such change, S227N, was reported for human isolates from Hong Kong in 2003.  This change increased the affinity for receptors found in the upper respiratory tract of humans, and decreased affinity for receptors found in birds.

Analysis of donor sequences in the Middle East identified donor sequences on H9N2, which is endemic to the Middle East.  Dual infections involving Qinghai H5N1 and H9N2 endemic in the Middle East, could generate S227N via recombination.  Therefore a warning was issued on October 22, 2005.  At that time, no human H5N1 infections involving the Qinghai strain had been reported.

In January, human H5N1 cases were reported in Turkey and H5N1 isolated from the index case was the Qinghai strain with the S227N acquisition.  Although S227N was not found in an isolate from the sister of the index case, it was found in a second human case from Turkey.  Thus, of the four human sequences released from Turkey, two had the S227N change.  WHO issued an update Febraury 20, 2006 indicating S227N had not been fixed in the Qinghai strain, but the number of human sequences released was limited to one case from Egypt, Iraq, and Djibouti.  Subsequently the sequence from one human case from Azerbaijan was also released.

However, the culture conditions can influence the isolation of H5N1 with receptor binding domain changes that favor binding to mammalian cells, which may have led to the failure to detect S227N in the isolate from the sister of the index case.  Similarly, the sequences of the receptor binding domain for most human cases in the Middle East have been withheld.

The release of eight sequences from Egyptians infected last spring has identified another Qinghai isolate, A/Egypt/2947/NAMRU3/2006 from the Middle East that has S227N.  Thus, the number of H5N1 Qinghai isolates with S227N has risen to three, but the total number remains unknown because most sequences outside of Egypt have not been released.  In Turkey 21 cases were H5N1 positive, bit only 12 were confirmed by Weybridge and only four sequences from these 12 confirmed cases were released.  Similarly, only one Azerbaijan sequence has been released and the role of culture conditions in the detection of S227N in the released sequences remains unclear.

Changes in the receptor binding domain can have significant effects of the ease of transmission from human to human.  Sequences released from birds in southern China identify additional changes.  An isolate from a duck from Shantou, A/goose/Shantou/2086/2006, has also changed position 227 from S--->R.  Moreover, the same isolate has a novel cleavage site, QRERRKKR, and two additional changes in or near the receptor binding domain, K222R and V223I.

The above changes significantly increase the likelihood of H5N1 increasing the efficiency of human to human transmission without decreasing the high case fatality rate, which remain causes for concern.

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