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M230I Alteration Near H5N1 Receptor Binding Doman in Egypt
Recombinomics Commentary
October 22, 2006

On October 11 the WHO update confirmed an H5N1 infection in a patient (39F) in the Gharbiya governorate in the Nile Delta.  Today the sequence of the HA gene from that patient was released, A/Egypt/12374-NAMRU3/2006(H5N1).  The rapid release of this sequence by the US Naval Medical Research Unit in Cairo is to be commended.  It was deposited at GenBank on October 13, 2006 and released shortly thereafter.

This Qinghai sequence has the common HA cleavage site, GERRRKKR, and has many polymorphisms found in isolates from birds and human cases from Egypt and Djibouti reported earlier this year.  However, the sequence also has an alteration, M230I, near the receptor binding domain.

Changes in the receptor binding domain are cause for concern because they can alter the ease of transmission.  Last year another change in the receptor binding domain, S227N, was predicted based on donor sequences in H9N2 in birds in the Middle East.  That change was found in the index case in Turkey, which was linked to a very large cluster.  Two of the four human sequences made public contained this change.

Changes in the receptor binding domain in the Qinghai strain are of additional concern because the Qinghai strain has already acquired a mammalian polymorphism, PB2 E627K.  This change increases polymerase activity at lower temperatures.  It offers strong selective advantage, and therefore is all in human H1, H2, and H3 isolates.  The acquisition by H5N1 was first reported in isolates from Qinghai Lake in China.  Subsequent isolates in Russia, Mongolia, Afghanistan, Turkey, Azerbaijan, Germany, Sudan, Italy, Croatia Slovenia, Niger, Nigeria, and the Ivory Coast in 2005 and 2006 has shown that this change has become fixed in the Qinghai strain.

Thus, additional changes in or near the receptor binding domain of Qinghai isolates are cause for concern.  Results of testing of additional suspect H5N1 patients in Egypt have not been announced.  However, H5N1 in Egypt may be further spread by migratory birds.

The change in the cleavage site has been reported in H5N2 birds from Mexico, as well as H5N1 from Vietnam.  Recombination between Clade 1 H5N1 in Vietnam and Clade 2 Qinghai H5N1 provides a mechanism for further genetic diversity in the Qinghai strain.  The Egypt isolates also have polymorphisms found in human H5N1 isolates in in Indonesia.  These acquisitions via recombination demonstrate additional genetic diversity.

The geographic expansion of H5N1 by wild birds in China as well as the Qinghai strain in Europe, the Middle East, and Africa, creates additional opportunities for recombination and added genetic diversity.

This added geographical reach, coupled with increased genetic diversity, are cause for concern.

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