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Public Health and Human WSN/33 in Swine on Korean Farms

Recombinomics Commentary
March 3, 2005

>>  Even if WSN were circulating in Korean pigs, Stöhr says, that wouldn't spell disaster. There's no evidence that WSN is still dangerous to humans, he says; indeed, Fouchier adds, many labs use it without taking special safety precautions. <<

The evidence that WSN/33 is dangerous to humans is based on genetic mutations and in vivo mouse experiments.  The same types of evidence  have fueled concerns over an impending flu pandemic.  However WSN/33 need not change to be efficiently transmitted human-to-human because it is a human flu virus.  It is a variant of the first flu virus ever isolated, in 1933.

If the sequences at GenBank represent the WSN/33 sequences in swine on Korean farms, then it has all of the hallmarks of the WSN/33 virus which is lethal and neurotropic in mice.  Two of the isolates from the swine are H1N1 and 7 of the 8 genes are over 99% homologous to WSN/33.  The isolates are missing the same glycosylation site on NA that allows the virus to sequester plasminogen and cleave the HA precursor.  Therefore it has broad tissue tropism and is neurotropic.  H5N1 has polybasic amino acids at the cleavage site, so although the mechanism is different, the end result is the same.  Both H5N1 and WSN/33 like viruses can efficiently cleave the HA precursor to gain entry into cells.

H5N1 has a 20 amino acid deletion in the NA protein and WSN/33 has a 16 amino acid deletion in the NA protein.  Both changes could reduce the effectiveness of Tamiflu which targets NA.  Although effective against H5N1, a higher dose is required for H1 than H2.  The H5N1 isolates from Vietnam and Thailand require higher doses than other N1 isolates to inhibit spread.

The other antiviral target is the M2 protein and both H5N1 and WSN/33 are resistant to ion channel blockers like Rimantadine and Amantadine.  Both have changes at position 31 and the H5N1 isolates from Vietnam and Thailand also have mutations at position 26.

H5N1 and WSN/33 also have a mutation at position 627 in PB2 that enhances virulence, although none of the swine isolates have this mutation.   Most have an avian PB2, and those that are recombinants in PB2 have avian sequences in the 3' end of the gene and are wild type at position 627.

One of the common assays for virulence is assayed by infecting mice.  Viruses that can grow in mice without adaptation are considered more virulent. The ability to grow in neurological tissues is another sign of virulence.  The H5N1 isolate from Vietnam that is being used to make a pandemic vaccine causes hind leg paralysis in ferrets.  WSN/33 is neurotropic and can be isolated from mouse brains.

Recent experiments with H and N genes from the 1918 pandemic virus used WSN/33 for the other 6 genes.  Both WSN/33 and WSN/33 with H and N from 1918 had similar in vivo killing ratios in mice.

Thus, WSN/33 has many of the properties that have caused concerns about an emerging H5N1 bird flu in Asia.  However, WSN/33 need not gain efficient human-to-human transmission, because it is a human flu virus and can be readily passed from human to human.

However, unlike contemporary human virus, WSN/33 has polymorphisms from 1933.  Therefore there are 60 amino acid differences between WSN/33 and the H1N1 used in current trivalent vaccines.  Similarly there are 45 amino acid differences in NA, excluding the 16 aa deletion in WSN/33.

In addition, the genes at GenBank are unstable.  The number of human genes in the 6 swine isolates is 7, 7, 5, 4, 4, and 3 demonstrating a great deal of reassortment.  Moreover, two of the genes, PB2 and NA, are recombinants.  PB2 is a human / avian recombinant while NA is an avian / avian recombinant.  Recent data also identifies H3N2, H9N2, H6N1, H5N1, and H5N2 circulating in Korea the last two years, providing more genes for recombination and / or reassortment.

Thus, if the WSN/33 sequences at GenBank represent WSN/33 genes in swine in Korea, there are many causes for concern.  Not only do the genes have a number of virulence markers and activities, but there are the unanswered questions concerning the path of human WSN/33 in a lab to human / avian recombinants and reassortants in many swine, on many farms in Korea.

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