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  • Resistant flu virus mutation to Relenza found in lab

    http://www.theage.com.au/national/re...0803-e79c.html


    Resistant flu virus mutation found
    Nick Miller
    August 4, 2009
    THE H1N1 flu virus has mutated into a form resistant to the Australian-developed antiviral drug Relenza.

    Researchers said the mutation posed little threat to humans yet: the virus was not a strain of swine or bird flu, and it was found only in the lab, not in patients.

    There are no known strains of Relenza-resistant influenza in humans. In contrast, virtually all the flu cases in the US and Europe last year, much of Australia’s seasonal flu and even a few cases of swine flu have proven resistant to the other leading antiviral drug, Tamiflu.

    A team at North Melbourne’s WHO Collaborating Centre for Reference and Research on Influenza analysed 391 influenza A(H1N1) viruses found in humans in Australasia and South-East Asia between 2006 and 2008, before the spread of swine flu.

    Nine of the viruses had a previously unseen mutation that made them 300 times more resistant to zanamivir (sold as Relenza), according to results reported in the Journal of Virology.

    The mutation was not found when the specimens were taken from patients, only later when the viruses multiplied in the lab.

    ‘‘That could mean there were very low levels of this mutation in the patient,’’ said Dr Ian Barr, one of the researchers involved and deputy director of the WHO centre. ‘‘We wouldn’t say it’s a clinical problem, but it’s an interesting finding. We know [the mutation] can survive, and it’s stable.’’

    The recent spread of Tamiflu-resistant A(H1N1) viruses showed that antiviral-resistant viruses could spread rapidly and travel widely around the world, the study authors warned.

    A spokeswoman for Biota, which developed Relenza, said the discovery was ‘‘not clinically relevant, because it’s an in vitro discovery — there’s no evidence that this mutation has infected patients’’.

    A spokeswoman for Relenza manufacturer GSK said the ‘‘clinical significance is yet to be determined’’.

    GSK announced a week ago that it planned to triple production of Relenza in the face of the spread of swine flu and rising demand from government stockpiles.

    Last week Japan identified its third case of Tamiflu-resistant swine flu, making a total of six worldwide.

    Scientists have warned that the massive worldwide use of Tamiflu since the outbreak of swine flu could hasten the spread of resistant mutations. No Relenza-resistant swine flu has yet been found.

  • #2
    Re: Resistant flu virus mutation to Relenza found in lab

    the position of the mutation is kept secret ?
    I'm interested in expert panflu damage estimates
    my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

    Comment


    • #3
      Re: Resistant flu virus mutation to Relenza found in lab

      Only from you gs!

      The reporter who left that detail out of this particular article did it just for you.

      (I'm off to read the "secret" location article, in my secret room, in my secret house, with my secret glasses)



      .
      "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

      Comment


      • #4
        Re: Resistant flu virus mutation to Relenza found in lab

        No secret ..it is in a lab

        Comment


        • #5
          Re: Resistant flu virus mutation to Relenza found in lab

          Originally posted by Sally View Post
          No secret ..it is in a lab
          And at least the 2 news articles I found in 2 minutes.

          .
          "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

          Comment


          • #6
            Re: Resistant flu virus mutation to Relenza found in lab

            Q--K:
            CAA-AAA
            CAG-AAG

            Q136K=C406A



            2679 N1 from genbank

            mutation in 10:

            A/Philippines/905/2006/05/30(H1N1)
            A/Philippines/1279/2006/06/26(H1N1)
            A/Philippines/604/2006/06/27(H1N1)
            A/Brisbane/297/2006/11/26(H1N1)
            A/Christchurch/62/2007/08/30(H1N1)
            A/Brisbane/308/2007/09/02(H1N1)
            A/Brisbane/334/2007/09/11(H1N1)
            A/Thailand/39/2008/01/02(H1N1)
            A/Macau/229/2008/02/21(H1N1)
            A/Managua/2055.01/2008/06/10(H1N1)


            the first 4 are Solomon-Islands/03 - like
            the last 6 are Brisbane/59 - like
            I'm interested in expert panflu damage estimates
            my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

            Comment


            • #7
              Re: Resistant flu virus mutation to Relenza found in lab

              PDF http://jvi.asm.org/cgi/reprint/JVI.01200-09v1.pdf

              Originally posted by ironorehopper View Post
              J Virol. 2009 Jul 29. [Epub ahead of print]

              Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation.

              Hurt AC, Holien JK, Parker M, Kelso A, Barr IG. - WHO Collaborating Centre for Reference and Research on Influenza, 10 Wreckyn St, North Melbourne, Victoria 3051, Australia; Monash University, School of Applied Sciences, Churchill, Victoria 3842, Australia; Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.


              The neuraminidase inhibitors zanamivir and oseltamivir are marketed for the treatment and prophylaxis of influenza, and have been stockpiled by many countries for use in a pandemic. Although recent surveillance has identified a striking increase in the frequency of oseltamivir resistant seasonal A(H1N1) viruses in Europe, USA, Oceania and South Africa, to date there have been no reports of significant zanamivir resistance among A(H1N1) viruses or any other human influenza viruses. We investigated the frequency of oseltamivir and zanamivir resistance in circulating seasonal A(H1N1) influenza viruses in Australasia and South East Asia. Analysis of 391 A(H1N1) influenza viruses isolated between 2006 and early 2008 from Australasia and South East Asia revealed nine viruses (2.3&#37 which demonstrated markedly reduced zanamivir susceptibility and contained a previously undescribed Gln136Lys (Q136K) neuraminidase mutation. The mutation had no effect on oseltamivir susceptibility, but caused approximately a 300-fold and a 70-fold reduction in zanamivir and peramivir susceptibility, respectively. The role of the Q136K mutation in conferring zanamivir resistance was confirmed using reverse genetics. Interestingly, the mutation was not detected in the primary clinical specimens from which these mutant isolates were grown, suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens or arose during MDCK cell culture passage. Compared to susceptible A(H1N1) viruses, the Q136K mutant strains displayed greater viral fitness than the wildtype virus in MDCK cells, but equivalent infectivity and transmissibility in a ferret model.

              PMID: 19641000 [PubMed - as supplied by publishe
              -
              ------

              Comment


              • #8
                Re: Resistant flu virus mutation to Relenza found in lab

                Originally posted by gsgs View Post
                the position of the mutation is kept secret ?
                Covered 2 years ago in Toronto, 1 year ago by Recombinomics

                <a rel="nofollow" href="http://www.recombinomics.com/News/07170803/Q136K_PA.html">Commentary</a>

                as well 3 days ago at flutrackers

                http://www.flutrackers.com/forum/sho...ighlight=q136k

                Comment


                • #9
                  Re: Resistant flu virus mutation to Relenza found in lab

                  Health officials said they had found cases of Tamiflu-resistant swine flu along the US border with Mexico, as India and South Africa announced their first deaths from the A(H1N1) virus.



                  "We have found resistance to Tamiflu on the border. We have observed some cases, few to be sure, in El Paso and close to McAllen, Texas," said Maria Teresa Cerqueira, head of the Pan-American Health Organization office in La Jolla, California.

                  Cases of A(H1N1) that were resistant to the anti-viral medicine have now been found in the United States, Canada, Denmark, Hong Kong and Japan.

                  Experts had gathered in La Jolla on Monday to discuss the response to the outbreak, and warned that resistant strains were likely emerging because of overuse of antivirals like Tamiflu.

                  "In the United States Tamiflu is sold with a prescription, but in Mexico and Canada it is sold freely and taken at the first sneeze. Then, when it is really needed, it doesn't work," said Cerqueira.

                  The Tamiflu-resistant cases were reported as South Africa and India both announced their first fatalities from the A(H1N1) virus, which emerged in Mexico in April and has since spread worldwide, gaining pandemic status.

                  In South Africa, health authorities said Ruan Muller, a 22-year-old student at Stellenbosch University near Cape Town, had died after contracting the virus.

                  "He died on the 28th (of July), but there had to be some testing done to ensure the cause of death. It was the A(H1N1) influenza," said Fidel Hadebe, spokesman for South Africa's Department of Health.

                  With the world's highest number of HIV/AIDS-affected people -- nearly 19 percent of a 49-million-person population -- South Africa is considered particularly at risk because people with compromised immunity are more likely to fall prey to the disease.

                  South Africa's swine flu caseload has increased fourfold since the country's first case was reported on June 14. The government has said its stockpile of Tamiflu will only be used for the seriously ill, but that schools may also be closed on a case-by-case basis.

                  In India, authorities said a 14-year-old girl in the western city of Pune became the country's first fatality from the virus.

                  The teenager first felt unwell on July 21, complaining of a sore throat, runny nose and headaches. She returned to school the following day after the general symptoms improved, the Ministry of Health and Family Welfare said.

                  She then developed a fever again on July 25 and two days later was admitted to a private clinic for treatment. She was put on a ventilator in an intensive care unit and was treated with Oseltamivir, a generic brand of Tamiflu.

                  "Her condition deteriorated again with multi-system involvement and (she) expired on the evening of 03.08.09," the ministry said in a statement.

                  Meanwhile, the Russian state health agency warned the country's football fans to stay away from the national team's World Cup qualifying tie with Wales in Cardiff on September 9.

                  "This would be an extremely unnecessary and inappropriate undertaking at a time of a flu epidemic," the head of Russia's state health agency Gennady Onishchenko said, according to local news agencies.

                  Onishchenko expressed fear that "the expressions of emotion on the part of football fans involving intense shouting" could lead to the airborne transmission of the flu virus.

                  Russia has to-date been relatively spared by the swine flu pandemic, with just 55 confirmed cases in the country.

                  Experts remain puzzled as to why different countries have not always been affected to the same degree, with England and Scotland both heavily hit proportionately, yet neighboring France's tally appearing light by comparison.

                  Some have argued that gargantuan sums being spent by rich economies on a disease that is no more lethal than seasonal flu are grotesquely disproportionate when thousands die each day of diseases which receive less media coverage.


                  http://uk.news.yahoo.com/18/20090804...t-5effa79.html

                  Comment


                  • #10
                    Re: Resistant flu virus mutation to Relenza found in lab

                    Originally posted by Sally View Post
                    contained a previously undescribed Gln136Lys (Q136K) neuraminidase mutation. The mutation had no effect on oseltamivir susceptibility, but caused approximately a 300-fold and a 70-fold reduction in zanamivir and peramivir susceptibility, respectively. The role of the Q136K mutation in conferring zanamivir resistance was confirmed using reverse genetics. Interestingly, the mutation was not detected in the primary clinical specimens from which these mutant isolates were grown, suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens or arose during MDCK cell culture passage. Compared to susceptible A(H1N1) viruses, the Q136K mutant strains displayed greater viral fitness than the wildtype virus in MDCK cells, but equivalent infectivity and transmissibility in a ferret model.
                    Hmm, "Previously undescribed" Q136K. Have these researchers heard of Google?

                    "suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens " So is this further evidence of mutations spreading "below the radar" of the consensus sequencers but you can find them if you look hard enough? Who's looking hard enough right now? (Pun not intended)

                    Comment


                    • #11
                      Re: Resistant flu virus mutation to Relenza found in lab

                      Originally posted by gsgs View Post
                      Q--K:
                      CAA-AAA
                      CAG-AAG

                      Q136K=C406A



                      2679 N1 from genbank

                      mutation in 10:

                      A/Philippines/905/2006/05/30(H1N1)
                      A/Philippines/1279/2006/06/26(H1N1)
                      A/Philippines/604/2006/06/27(H1N1)
                      A/Brisbane/297/2006/11/26(H1N1)
                      A/Christchurch/62/2007/08/30(H1N1)
                      A/Brisbane/308/2007/09/02(H1N1)
                      A/Brisbane/334/2007/09/11(H1N1)
                      A/Thailand/39/2008/01/02(H1N1)
                      A/Macau/229/2008/02/21(H1N1)
                      A/Managua/2055.01/2008/06/10(H1N1)


                      the first 4 are Solomon-Islands/03 - like
                      the last 6 are Brisbane/59 - like
                      Eight were at Genbank over a year ago

                      <a rel="nofollow" href="http://www.recombinomics.com/News/07170803/Q136K_PA.html">Commentary</a>

                      Clade 2B (Brisbane)
                      A/Thailand/39/2008
                      A/Christchurch/62/2007
                      A/Brisbane/308/2007
                      A/Brisbane/334/2007

                      Clade 2A (Solomon Island)
                      A/Philippines/905/2006
                      A/Philippines/604/2006
                      A/Philippines/1279/2006
                      A/Brisbane/297/2006
                      in addition to the sequence from PA, which was a mixture. However, even though the mixture was in a published sequence generated by the CDC, the CDC claimed no Relenza resistance in the US in the 2007/2008 season.

                      Comment


                      • #12
                        Re: Resistant flu virus mutation to Relenza found in lab

                        Updated travel log

                        gb|CY040228.1| Influenza A virus (A/Managua/2055.01/2008(H1N1... 34.2 2.9
                        gb|FJ899925.1| Influenza A virus (A/Macau/229/2008(H1N1)) seg... 34.2 2.9
                        gb|CY030877.1| Influenza A virus (A/Christchurch/62/2007(H1N1... 34.2 2.9
                        gb|CY030875.1| Influenza A virus (A/Brisbane/308/2007(H1N1)) ... 34.2 2.9
                        gb|CY030873.1| Influenza A virus (A/Thailand/39/2008(H1N1)) s... 34.2 2.9
                        gb|CY030871.1| Influenza A virus (A/Brisbane/334/2007(H1N1)) ... 34.2 2.9
                        gb|CY030868.1| Influenza A virus (A/Philippines/905/2006(H1N1... 34.2 2.9
                        gb|CY030866.1| Influenza A virus (A/Philippines/604/2006(H1N1... 34.2 2.9
                        gb|CY030864.1| Influenza A virus (A/Philippines/1279/2006(H1N... 34.2 2.9
                        gb|EU124179.1| Influenza A virus (A/Brisbane/297/2006(H1N1)) ... 34.2 2.9

                        Comment


                        • #13
                          Re: Resistant flu virus mutation to Relenza found in lab

                          so not so new as it appears in the article.

                          > A spokeswoman for Biota : "not clinically relevant"
                          > A spokeswoman for GSK : ‘‘clinical significance is yet to be determined’’

                          she should ask the other spokeswoman ;-)

                          > triple production of Relenza

                          ask the spokeswoman of Daiichi Sankyo about CS-8958
                          I'm interested in expert panflu damage estimates
                          my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

                          Comment


                          • #14
                            Re: Resistant flu virus mutation to Relenza found in lab

                            Originally posted by Hogweed View Post
                            Hmm, "Previously undescribed" Q136K. Have these researchers heard of Google?

                            "suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens " So is this further evidence of mutations spreading "below the radar" of the consensus sequencers but you can find them if you look hard enough? Who's looking hard enough right now? (Pun not intended)
                            Exactly right. Both Q136K and H274Y are silently spreading (no head pats required).

                            Comment


                            • #15
                              Re: Resistant flu virus mutation to Relenza found in lab

                              The point has been made elsewhere that a virus genome of N nucleotides in length can have 4 to the power N possible nucleotide combinations. The influenza A virus (with A 12Kb genome) thus has 4 to the power 12,000 possible combinations. Apparently, there are are a 'mere' 10 to the power 80 protons in the entire universe!!!

                              Clearly a very large subset of the possible genomic combinations for influenza A H1N1 will be dysfunctional, but given the massive production of progeny viruses and the great redundancy of polymerase, it is, I venture, highly probable that out there at this very moment there is at least one (and probably many more) representive, fit H1N1 genomes confering resistance to everyone of the anti-virals and vaccines that have ever been invented or ever will be invented.

                              Happily it seems, H1N1 viruses with Q136K are relativey infrequent at this time compared to H274Y for whatever reason. If the vaccine turns out to be poorly matched to an evolved, highly lethal swine flu, GSK, in tripling its production of Relenza, and Sankyo coming through with the LANIs, I suggest are very welcome events - albeit later than desirable. The world desperately needs alternative antivirals to Tamiflu at this time - but let's face it all drugs and vaccines will at some point will be out-manoevered by the viruses.

                              The opportunity for pushing flu viruses over the error threshold and into extinction is about as likely as Eddie the Eagle winning gold at the next winter Olympics.

                              ...And that's why we should celebrate the (selfish) profit motive and the opportunity for patent monopoly - to encourage entrepeneurs to fund the research to invent new drugs. A viruse's best friend is a commie.
                              Last edited by ARR_309; August 5th, 2009, 05:17 AM. Reason: math edit

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