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Fixing S227N and Acquiring G228S in Avian H5N1 in Europe
Recombinomics Commentary
February 21, 2006
Viruses from Qinghai Lake showed a distinctive mutation at one site experimentally associated with greater lethality in birds and mice. Viruses from the most recent outbreaks, in Nigeria, Iraq, and Turkey, as well as from earlier outbreaks in Russia, Kazakhstan, and Mongolia, are virtually identical to Qinghai Lake viruses.
Some mutations have been detected in human viruses isolated in 2005 and, most recently, in one virus isolated from a fatal case in the January 2006 outbreak in Turkey. Although these mutations were found at the receptor-binding site and involved the substitution of more mammalian-like amino acids, the effect of these changes on transmissibility of the virus, either from birds to humans or from one person to another, is not fully understood. Moreover, recent studies show that these mutations were transient and did not become fixed in the circulating viruses.
The above comments from the WHO update on address two well known changes in the Qinghai strain of H5N1, PB2 E627K and HA S227N. The Qinghai strain has been transported and transmitted by long range migratory birds.
The strain has a characteristic poly-basic cleavage site of GERRRKKR. The sequence was first reported in isolates from two duck from Hong Kong in 2004, A/Duck/Hong Kong/ww487/2000 and A/Duck/Hong Kong/ww461/2000. More recently, it was in two 2004 chicken isolates in Hubei, A/Chicken/Hubei/14/2004 and A/chick/Macheng/2004. In 2005, three for the six migratory bird isolates from Jiangxi (A/migratory duck/Jiangxi/2136/2005, A/migratory duck/Jiangxi/2295/2005, A/migratory duck/Jiangxi/2300/2005). The polymorphism became fixed at Qinghai lake and was found in all 16 isolates. This change was found in isolates from each country reporting the Qinghai stain in 2005 and 2006.
Another polymorphism that was fixed at Qinghai Lake was PB2 E627K. This polymorphism has been found in all human isolates with the common human serotype (H1, H2, H3). The isolates at Qinghai Lake were the first reported E627K in H5N1 from birds. The polymorphsim was in all 16 isolates and present in all subsequent reported isolates, which are listed below
A/bar-headed goose/Mongolia/1/05
A/chicken/Kurgan/3/2005
A/Cygnus olor/Astrakhan/Ast05-2-2/2005
A/Cygnus olor/Astrakhan/Ast05-2-3/2005
A/Cygnus olor/Astrakhan/Ast05-2-4/2005
A/Cygnus olor/Astrakhan/Ast05-2-5/2005
A/Cygnus olor/Astrakhan/Ast05-2-6/2005
A/Cygnus olor/Astrakhan/Ast05-2-7/2005
A/duck/Novosibirsk/56/2005
A/Environment/Qinghai/31/2005
A/grebe/Novosibirsk/29/2005
A/whooper swan/Mongolia/3/05
A/whooper swan/Mongolia/4/05
A/whooper swan/Mongolia/6/05
The E627K was associated with increased virulence in mammals, and the change was associated with increased activity at 33 C. Although the Qinghai isolate was highly virulent in experimental chickens and mice, there were no human cases associated with any of the above isolates or infections in Romania, Croatia, Ukraine, or Western Turkey.
The migration of H5N1 into the Middle East however, created an opportunity for the acquisition of S227N via recombination with indigenous H9N2. The first human case was reported at the end of 2005 and confirmed shortly thereafter. Isolates from the index case contained S227N, which had been previously reported to have an increased affinity for human receptors. The index case in Turkey was linked to the largest familial cluster linked to H5N1. Three siblings were hospitalized with bird flu symptoms. Two were confirmed to be H5N1 positive after their death. Ten members of a related family were hospitalized and H5N1 was confirmed in two. Two members of a third related family were hospitalized and both were confirmed to be H5N1 positive and one died.
Media reports indicated that S227N was not detected in an isolate from one of the siblings. However, isolation of H5N1 with S227N can be dependent on the isolation procedure. Other polymorphisms with increased affinity for mammalian receptors are lost when virus is isolated in chicken eggs. The S227N positive isolates from Hong Kong in 2003 were isolated in mammalian MDCK cells. Moreover, since S227N was identified in the Qinghai strain in Turkey for the first time, it would not be expected to be in all isolates. However, additional familial clusters were identified in Turkey as well as northern Iraq, suggesting S227N was present and transported and transmitted by wild birds.
Migration of H5N1 into western Europe may generate additional acquisitions of polymorphisms that have increased affinity for mammalian receptors. European swine H1N1 isolates have donor sequences for the acquisition of G228S. Thus, it is possible that H5N1 with and without S227N will migrate into western Europe. There have already been recent reports of H5N1 in western Europe. However, more H5N1 is expect to migrate north from Africa via the East Atlantic Flyway, creating additional opportunities for recombination and acquisition of G228S.
Immunization of swine against H1 and H5 may be warranted, as the number of H5N1 infected birds increase in western Europe in the upcoming months.
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