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Here’s the latest by Dr. Henry Niman. I’ve made a few helpful comments in red. – Ilene

D225E and D225N H1N1 RBD Changes in Turkey

Courtesy of Henry Niman, PhD

Swine flu virus, showing the structure of the virion: the outer proteins hemagglutinin and

Recombinomics Commentary
January 5, 2010

The Refik Saydam National Public Health Agency has released 29 HA [hemagglutinin] sequences from Ankara, Turkey. Several were partial sequences, but 26 covered the receptor binding domain and 8 had D225E,… while one had D225N,… 

My comment:  D225 is the most common or wild-type receptor binding protein – the hemagglutinin (HA) protein – which enables the virus to bind to tissues in the respiratory tract of infected people. 

A change in the amino acid in position 225 of the receptor binding domain (RBD) is symbolized by using the letter representing the new amino acid, e.g. "G" for glycine in "D225G." The marker D225G signifies that a glycine (G) is present in the 225 position, replacing the amino acid usually in this position, aspartic acid, or D (hence the wild-type marker is "D225"). Glutamic acid, E, and asparagine, N, are two other amino acids that have been found in this position in non-wild-type swine flu viruses.

The change in the receptor binding protein from D to G alters the protein’s preference for binding to human tissues. Viruses with the D225G marker bind in the lung tissue, rather than binding in the upper respiratory tract (nasal area and throat), the more typical target. This appears to result in more severe disesase which may trigger a "cytokine storm" reaction in the lungs.  Whether substitution with "E" or "N" causes similar changes is not known. Theoretically, if the immune response is generated against the wild-type protein D225, viruses with D225G, D225E or D225N markers might avoid the immune system’s response. 

[Back to Dr. Niman] The outcomes of these patients were not given but media reports have described a rapid in increase in H1N1 fatalities in Turkey.  A large number of HA sequences with D225E has been published from Spain, and recently released GISAID sequences from Sweden and the UK also have D225E, including three fatal cases from Sweden. The prior reports of D225G and D225N associations with fatal cases has raised concerns that changes at position 225 could alter tissue tropism or aid in immune escape, leading to more severe and fatal cases.

In addition, the first reported cases of H274Y [marker for tamiflu resistance] in an H1N1 patient who had not been treated with Tamiflu also had D225E as did another H274Y isolate from Tennessee, raising concerns that H274Y would pair up with receptor binding domain changes and become fixed, as happened with H274Y in seasonal H1N1.

The genetic change leading to tamiflu resistance spread quickly throughout the pool of seasonal H1N1 flu viruses (where the HA protein is from human rather than swine origin). This can potentially be repeated in the swine flu virus.

In addition to the large number of isolates with D225E, the isolate with D225N has an additional marker that matches recent sequences from Russia and Denmark.  Two of the Russian isolates were fatal and those sequences had D225G.  The presence of D225G and D225N on similar backgrounds [in viruses closely related genetically] raises concerns that these isolates are mixtures, as seen in patients in Mexico, United States, and Sweden, where both D225G and D225N were present.

…The increasing presence of these changes at position 225 continues to raise concerns that these changes will lead to increased Tamiflu resistance, severe cases, and fatalities in the next pandemic H1N1 wave, which may begin in the next few weeks.

These changes are natural occurrences. Dr. Niman predicted changes like these would occur due to recombination, a natural process in flu virus evolution.   More studies need to be done to determine the significance of these genetic changes.


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