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Qinghai H5N1 Acquisitions Via Recombination

Recombinomics Commentary
April 16, 2007

The recent NA sequences from patients in Egypt provide compelling evidence for the acquisition of H5N1 polymorphisms via recombination.  Like all H5N1 highly pathogenic avian influenza in countries west of China, the isolates in Egypt are the Clade 2.2 Qinghai strain. This strain was first reported at Qinghai Lake in May, 2005.  The strain was easily distinguished from H5N1 in poultry and patients in Asia.  It had a novel HA cleavage site of GERRRKKR and had PB2 E627K.  The presence of E627K was alarming, because the polymorphism had never been reported in H5N1 from birds, but was in all initial isolates at Qinghai Lake.

E627K is in all human seasonal flu isolates dating back to the H1N1 pandemic strain in 1918.  It was in all human H1N1, H2N2, and H3N2 isolates.  In contrast, avian H5N1 isolates had 627E.  E627K in H5N1 isolates prior to Qinghai Lake had been in a subset of human cases dating back to the 1997 Hong Kong outbreak, as well as human isolates in Vietnam and Thailand.  It had also been found in H5N1 passages through mouse brains, as well as H5N1 infected tigers at a zoo in Thailand.  The linkage to mammals was likely associated with the increased polymerase activity of E627K which was greatest at 33 C.  In contrast activity of 627E was highest at 41 C.

Clade 2.2 isolates were subsequently found in Siberia at Chany Lake as well as adjacent locations in Kazakhstan and Erhel Lake in northern Mongolia.  H5N1 had not been previously reported in any of these regions and the reports in the summer of 2005 provided compelling data for the transport and transmission by long range migratory birds.

The H5N1 was expected to migrate into Europe, the Middle East, and Africa, providing an “experiment of nature” for the analysis of the evolution of H5N1.  In the fall of 2005, H5N1 was reported in Romania and western Turkey.  The H5N1 was the Qinghai strain with associated markers.  However, the genetic background in isolates from these new introductions were linked to the region, and polymorphism tracing defined travel routes as well as acquisitions found in H5N1 isolates in eastern Asia, as well as low path isolates in Europe and Asia.  In early 2006, human H5N1 cases were reported in Turkey, Iraq, Azerbaijan, Egypt, and Djibouti.  Like the wild bird and poultry isolates, the human isolates also had regional markers.

US NAMRU-3 in Cairo collected a large series of human and bird isolates in the 2005 / 2006 season as well as isolates from the 2006 / 2007 season.  These isolates provided a molecular clock of H5N1 evolution.  The more recent isolates had additional genetic complexity and the regional markers that were present in early 2006, were present in the 2006/2007 isolates.  The newly acquired markers frequently had not been seen previously in human Qinghai isolates, but had been present in avian Qinghai isolates from the prior season or recent H5N1 isolates from eastern Asia.  In several instances, the newly acquired markers created discordance with the earlier Qinghai sequences, providing evidence for recombination.

However, the recent human NA sequences from Egypt contained G743A, which not only was discordant with the previous Qinghai sequences from northern Germany, but the newly acquired polymorphism appeared simultaneously on three different genetic backgrounds in Egypt, as well as another Qinghai background in Moscow.

The polymorphism was in 23 isolates from Germany collected a year earlier.  The German isolates formed a large subset from Germany that had regional markers in the public HA and NA sequences.  In contrast, the isolates in Egypt had Egyptian regional markers, while the Moscow isolates had Azerbaijan regional markers in the HA and NA sequences.  Thus, the newly acquired marker in Germany in early 2006, appeared on four different genetic backgrounds in early 2007. 

This simultaneous appearance on multiple genetic backgrounds is most easily explained by recombination with a common source with G743A.

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