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Human and Bird Flu Recombination and Reassortment in Korea

Recombinomics Commentary

January 4, 2005

>> In other words, researchers will be engineering viruses of pandemic potential. It's high-risk but crucial work, the influenza community insists.<<

Much of the critical work has already been done in Korean swine, although such work has yet to be acknowledged by the World Health Organization (WHO), even though they were notified of the "experiment" almost a month ago.

The planned Center for Disease Control and Prevention (CDC) experiment will infect the same cells with and avian virus (H5N1) and a human virus (H1N1 and/or H3N2).  The chief drawback from such a procedure is selection pressure.  The viruses will surely recombine (mix and match pieces of gene to make new genes) and reassort (shuffle the existing genes to create new viruses which different combinations of avian and human flu genes), but the emerging viruses will be driven by selection pressures.

This "experiment" has been done in nature in Korean swine.  The human flu virus was WSN/33, a popular flu virus carried by many laboratories around the world.  It was derived from WS/33, the first human flu virus ever isolated.  WS/33 came from a London physician, Christopher Mathewes who came down with the flu in London in 1933.  Wilson Smith successfully infected ferrets with virus from a nasal swab and isolated the virus, named WS/33, described in Lancet that year.

In 1940 WS/33 was used to infect laboratory mice because many of the fatalities in the 1918 flu pandemic included patients with neurological symptoms.  WSN/33 was isolated from the brains of fatally infected mice.  The derivative was named WSN (Wilson Smith Neurotropic)/33 (the year of original isolation).  The virus became popular in labs because it was neurotropic, virulent, and grew in tissue culture.  Its ability to grow in tissue culture was attributed to a mutation in the neuraminidase gene, which abolished a glycosylation site.  This mutation allowed the virus to sequester plasminogen, a precursor to a protease in plasma,  When activated, this protease will cleave the hemagglutinin precursor into HA1 and HA2, which is required for the virus to infect cells.  This ability to use plasminogen allows the virus to grow in tissue culture, mice, and a variety of tissue types.

Recent, WSN/33 found its way from a lab somewhere into swine in Korea.  It appears to have acquired some contemporary mammalian polymorphisms through recombination (swimanization).  It then generated the CDC experiment in swine, recombining and reassorting with Korean bird flu viruses (H9N2).  The six swine isolates,
A/swine/Korea/S10/2004(H1N1), A/swine/Korea/S175/2004(H1N1), A/swine/Korea/S81/2004(H9N2), A/swine/Korea/S83/2004(H9N2), A/swine/Korea/S109/2004(H9N2), A/swine/Korea/S190/2004(H9N2) with WSN/33 genes have been deposited at GenBank.

Analysis of those sequences show that the various viruses have done a considerable amount of recombining and reassorting.  Two of the viruses are H1N1 and contained many of the tell tale markers such as the missing glycosylation site and a 16 amino acid deletion in NA, a 1 amino acid deletion in HA, and a mutation in the M gene that altered position 31 in the M2 proetin and made the virus resistant to amantadine and rimantadine.  In these two instances, 7 of the 8 genes are from WSN/33 (each is over 99% homologous to WSN/33).  In both cases, the PB2 gene is from a Korean avian virus (H9N2).  The other four isolates are H9N2. Of the remaining 6 genes, these isolates have 5,4, or 3 WSN/33 genes demonstrating several combinations of reassortment.

However, in addition to this reassortment, there has been a considerable amount of additional recombination.  Two of the H9N2 isolates have a recombined PB2 gene with the 5' half from WSN/33 and the 3' half from an avian H9N2.  The cross over point differs by 25 nt.  In addition, there is recombination in the N2 gene involving two Korean avian sources.  The are several different cross over points, generating various combinations of N2 genes.

Thus, the CDC experiment has already been done, but it was done in swine on farms in Korea.  The ability of each of these recombined and reassorted isolates to cause disease and birds, humans, and mice remains to be seen (the swine has respiratory infections).

However, these viruses appear to be spreading and alerts have yet to be issued.

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