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influenza NS1 segment - positions 103 and 106

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  • influenza NS1 segment - positions 103 and 106

    Of the many mutations that effect virulence, NS1 103 & 106 had values in A/Hong Kong/483/97 (HK97) that are the same as China's human H7N9/2013, i.e., "L" and "I". As of 2003 the human H5N1 values had changed to the concensus "F" and "M", but during the intervening years there was a mixture of the 2 versions in birds (as shown in GenBank sequences). The following paper discusses the implications of these changes:

    The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins

    ABSTRACT

    The NS1 protein of human influenza A viruses binds the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a protein required for 3′ end processing of cellular pre-mRNAs, thereby inhibiting production of beta interferon (IFN-β) mRNA. The NS1 proteins of pathogenic 1997 H5N1 viruses contain the CPSF30-binding site but lack the consensus amino acids at positions 103 and 106, F and M, respectively, that are required for the stabilization of CPSF30 binding, resulting in nonoptimal CPSF30 binding in infected cells. Here we have demonstrated that strengthening CPSF30 binding, by changing positions 103 and 106 in the 1997 H5N1 NS1 protein to the consensus amino acids, results in a remarkable 300-fold increase in the lethality of the virus in mice. Unexpectedly, this increase in virulence is not associated with increased lung pathology but rather is characterized by faster systemic spread of the virus, particularly to the brain, where increased replication and severe pathology occur. This increased spread is associated with increased cytokine and chemokine levels in extrapulmonary tissues. We conclude that strengthening CPSF30 binding by the NS1 protein of 1997 H5N1 viruses enhances virulence in mice by increasing the systemic spread of the virus from the lungs, particularly to the brain.

    (snipped)

    ...Both structural and nonstructural gene products have been reported to contribute to the enhanced replication and virulence of H5N1 in mammalian animal models...

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    Whether or not 2013/H7N9 will follow the same pattern and eventually change to 103F and 106M with similar results as discussed above only time will tell. But the details may shed some light on understanding this new virus.

    .
    "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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