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Novosibirsk Russia and Qinghai Lake China H5N1's are Similar

Recombinomics Commentary

August 11, 2005

Genetic sequencing of a particular fragment of the virus relating to its virulence shows it is "analogous to the sequence of the highly virulent [H5N1 sub-type] found in three species of migratory water birds during the epidemic in May and June on Qinghai Lake in China, writes Evgueny Nepoklonov, head of the main veterinary department at the Russian ministry.

The turkey virus was also subjected to a phylogenetic analysis, which shows evolutionary history, of a crucial flu gene - the neuraminidase gene. This provides additional evidence of link to the Chinese migratory bird outbreak. "The preliminary data on the neuraminidase structure show that it is practically identical to that of the isolate from bar-headed geese (Anser indicus) from Qinghai Lake," says Nepoklonov.

The above comments on sequences from H5N1 isolated in the Chany Lake region of Novosibirsk leave little doubt that the H5N1 bird flu was brought to the Chany Lake nature reserve via migratory birds (see map).  The sequences match in three key genes, the HA cleavage site, the sequences of the NA gene, and a virulence fragment, which is almost certainly the PB2 polymorphism, E627K striongly suggests that H5N1 migrated from Qinghai Lake to Chany Lake.

These data are cause for concern for many reasons.  First it is clear that the unique genetic sequences seen at Qinghai Lake did not burn out when over 6000 water fowl died.  The isolates from Qinghai lake were particularly virulent, killing test chickens in 20 hours and mice in 3-4 days.  The virulence in mice correlated with E627K, which was found in all 16 sequences deposited at GenBank.  Prior to sequences from Qinghai Lake, E627K had never been isolated in H5N1 from a bird.  Previous H5N1 isolates had been in variants that had grown in mouse brains.  The change was also found in tigers in Thailand and patients from Hong Kong, Thailand, and Vietnam. The E627K was associated with a poor outcome.  In contrast, E627K is found in all human isolates that date back to the first human isolate in 1933.  The acquisition of mammalian sequences by H5N1 is associated with increased ability to cause human infections.

The E627K is also associated with neurological problems.  H5N1 with that change have been isolated from the brains of mice.  It was also found in the Thailand tigers, which also had neurological problems. The change is also in the 2004 H5N1 being used to test Tamiflu and create a pandemic vaccine.  That H5N1 causes hind leg paralysis in ferrets and mice that died in the Tamiflu experiment had H5N1 in their brian.

The similarity of the NA between Qingahi Lake and Novisibirsk isolates suggest that the pandemic vaccine being developed worldwide will have little effect on the H5N1 being transported by migratory birds.  The NA of the Qinghai Lake isolates differed from the 2004 isolate from Vietnam by 13 amino acids.  The HA from Qinghai lake has an even greater number of amino acid differences, 18.

Similarly, since Tamiflu targets NA, the near identity between the Novosibirsk and Qinghai isolates and their close relationship to NA from Vietnam suggest that more testing of Tamiflu will be required to determine the optimal does for treating or preventing H5N1 infections.

On a positive note, the similarities between the Novisbirsk and Qinghai isolates suggests that the M2 in migratory bird isolates will be sensitive to amantadine and rimantadine, although there are side effects and resistance has developed in the past.  However, the two anti-viral agents are available in quantity in generic form, so the cost is markedly less than Tamiflu.


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