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H5N1 Receptor Binding Domain Recombination

Recombinomics Commentary 17:35
April 13, 2008

The recent media reports on H5N1 human to human transmission in China and Pakistan, as well as a new combination of receptor binding domain changes involved in a switch from affinity to an avian receptor to a human receptor has focused attention on Egypt, where the largest number of receptor binding domain changes have been reported. 

Egypt has the highest number of H5N1 cases outside of Asia, and recently released sequences on vaccinated flocks (by Egypt’s National Veterinary Labs - NLQP) have identified a large number of non-synonymous changes, including a change at position 230 (M230V).  Previously, another change at position 230, M230I, had been found in multiple cases in Egypt last season, and all such cases were fatal.  This season, the confirmed cases have all progressed to a critical state.  Four of the five cases at the end of 2007 died, and half of the more recent cases this year have also died, including the two most recently confirmed cases.  The association of receptor binding domain changes in this season’s cases is unclear because none of the sequences from these cases have been released, even though the December cases died over 3 months ago.

However, the homologous recombination of receptor binding domain changes was seen last season, and there are more examples in poultry this season.  The first case in the 2006/2007 season died and had M230I.  This change had been previously seen in an eagle owl Qinghai H5N1 sequences from Germany in early 2006.  The first human case in Egypt was followed by a cluster of cases in Gharbiya.  H5N1 was isolated from two of the three family members fatally infected with H5N1, and these isolates also had M230I as well as another receptor binding domain change V223I.  This change had been previously seen in a Qinghai isolate from Mongolia in 2005.  The presence of both receptor binding domain changes on an Egyptian genetic background signaled acquisition by recombination.  This mechanism recombines pieces of genes to create new genetic entities, and this mechanism is cause for concern because of additional receptor binding domain changes reported previously in the region.

A change at position 227, S227N, was initially reported in Turkey, but was subsequently found appended onto an Egyptian genetic background in the 2005/2006 season as well as the 2006/2007 season (and no human sequence data has been released for the 2007/2008 season).  Similarly, changes at positions 186 and 196 had been reported earlier in Azerbaijan and Iraq.  As noted above, M230V has also been reported in poultry isolates.

The combination of V223I and M230I was not limited to the Gharbiya cluster last season.  This combination was subsequently found in poultry isolates in Gharbiya and Beni Suef in early 2007.  The recently released poultry sequences by NAMRU-3 include multiple poultry sequences with both V223I and M230I.  The sequences have already eliminated the glycosylation site at position 158 and have acquired the original HA cleavage site RERRRKKR, which was reported in 1996 in a Guangdong goose.  This acquisition on an Egyptian genetic background signals another recombination event.

Recombination is dependent on co-infections.  In Egypt, the concentration of poultry and people in the Nile Delta as well as along the Nile River creates an environment for co-infections.  Similarly, the location of these areas within two overlapping migratory bird flyways creates conditions that favor new acquisitions via recombination.  Recently released sequences from a tiger from Shanghai have multiple polymorphisms that were acquired by isolates in Egypt last season, signalling the range of movement of these polymorphisms.

Thus, the circumstances in Egypt favor rapid evolution via recombination, including an acceleration of receptor binding domain roulette, which remains hazardous to the world’s health.

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