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Nature - HA mutations responsible for the binding of H5N1 A viruses

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  • #46
    Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

    Originally posted by gsgs
    just like anything else is "unpredictable".
    Just some events can be reasonbly considered more likely than others.
    We still have our probability estimates for any future event.

    And Osterholm (and others) frequently say, that another pandemic
    is 100% sure (no timeframe) . For me it's only 95%.
    I agree that the probability of another pandemic occuring at some point in the future is 100%. However, since no one can quantify this absolutely, it is unpredictable.

    Comment


    • #47
      Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

      Originally posted by vinny
      thank you dr niman for answering my question.can i ask one more question please,when you said in your reply, more to come this winter do you mean the human pandemic.??
      The "more to come", is additional evidence that the human pandmeic is getting closer. Although predicting the say or month is difficult, most chnages are linked to recombination with H5 sequences in migratory birds, and most of the chnages happens in the fall/winter.

      Thus, more to come includes H5N1 spread to North Amrica (which will be moree evident in sequences than actual isoaltes, because most of teh effort in the US and Canada is on live birds and the assays are not very sensitive. The number of dead birds being tested is MUCH lower than live birds. Most countries in Europe detected H5N1 in dead birds, and many of those countrioes with H5N1 in Europe, have yet to report H5N1 in poultry.


      There will also be more human cases, although reporting of such cases in Africa, is still poor.

      There will also be more examples of chnages in the receptor binding domain sequences, but these will also come after the fact (possibly LONG after the fact, because the sequences are being withheld, and bird isolates select against detection of such changes).

      Thus, the "more to come" will add fuel to the fire, but it may or may not produce a dramatic jump in reported human cases.

      Comment


      • #48
        Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

        Commentary at

        http://www.recombinomics.com/News/11...do_Pledge.html

        Comment


        • #49
          Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

          Originally posted by niman
          United States Pledges Increase in H5N1 Support in Indonesia
          Recombinomics Commentary
          November 20, 2006

          The two Presidents discussed the grave threat posed by Avian Influenza (AI), and President Yudhoyono reiterated his Government's firm commitment to combating its spread. He briefed President Bush on Indonesia's completion of a unified national response plan, increase in the AI budget for 2007, and active participation in the International Partnership on Avian and Pandemic Influenza. President Bush announced the United States would increase its AI assistance to Indonesia to expand animal surveillance and response efforts and strengthen nation-wide public awareness. President Bush confirmed that the U.S. Centers for Disease Control and Prevention and Animal and Plant H
          ealth Inspection Service would assign permanent staff to Indonesia to build more effective partnerships with their counterparts in Indonesia. President Yudhoyono thanked President Bush for the United States' work in support of the Indonesian Ministry of Health's efforts to identify human AI cases and investigate AI outbreaks. The two Presidents stressed the imperative of continued and enhanced cooperation between Indonesian and American health workers and medical scientists to fight infectious diseases, including through the Naval Medical Research Unit (NAMRU-2), which has been in operation since 1968. They agreed that negotiations to extend the research work of NAMRU-2 should be expedited.

          The above comments reaffirm the concerns about H5N1 bird flu in Indonesia and pledge additional support and expanded testing. However, after more than a year of analysis of H5N1 human patients in Indonesia, major questions on the origin and spread of human H5N1 remain.

          The first human H5N1 was isolated in July of 2005 and had a novel cleavage site, RESRRKKR, as well as a number of associated genetic changes. From July 2005 to the present, the vast majority of human H5N1 has had these sequences. There have only been two exceptions, the second confirmed human H5N1 Indonesian case, and the Karo clusters. Isolates from the remaining cases have come from areas throughout Java, but primarily in regions of western Java, including the Jakarta area.

          These human H5N1 sequences have failed to match poultry H5N1. The match failure was noted in the H5N1 meeting in Jakarta in July, 2006. Since the failure might have been due to collection dates, 91 samples were sent to a WHO-affiliated lab in Australia. The vast majority of the poultry isolates, collected between the fall of 2005 and spring of 2006 also failed to match the human sequences. On isolate on the island of Java from a duck in Indramayu had the novel cleavage site, but only matched a small subset of human cases from late 2005. They only two avian matches for the human cases on Java were from two chickens on Sumatra. The only non-human match on Java for the cases there was from a cat in Indramayu, which matched the human cases on Java, including the cases from Indramayu.

          The match failures in poultry suggest H5N1 is evolving in a separate reservoir, which likely involves wild birds and a mammalian reservoir on Java.

          Recent data has pointed toward the acquisition of mammalian polymorphisms that affect receptor binding. Although these changes have been found in H5N1 in human cases in Vietnam and Thailand, as well as human cases in the Middle East, they have not been found in human isolates from Indonesia. However, human samples from H5N1 patients have been sent to the CDC and Hong Kong, but the human H5N1 has been isolated in chicken eggs, which would select against mammalian specific changes in the receptor binding domain.

          Determining the source of human H5N1 in Indonesia as well as the isolation of human H5N1 on mammalian cells, should be top priorities of the increased effort described above.

          Media sources

          Phylogenetic Trees
          http://novel-infectious-diseases.blogspot.com/

          Comment


          • #50
            Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

            Originally posted by Florida1
            I agree that the probability of another pandemic occuring at some point in the future is 100%. However, since no one can quantify this absolutely, it is unpredictable.
            Dramatic progress towards a forecasting system for influenza continues to occur.

            Taubenberger's seminal identification of the characteristics of the prior major pandemic within the past 100 years has helped.

            Recent Japanese recognition of sequence commonalities with 1918 is another piece of the factual pie.

            Niman's homologous recombination "theory" when (and if) proven in AI will be another piece of predictive logic.

            And when IBM and Scripps stop looking backwards, their proposed project, for which they're seeking a mere $500 million bux, could be the backbone tool for running the probabilties.

            This time, we don't know how it happens. Next time, there may be a way to save the world, by forecasting the type of flu's that have the then current probability of becoming Phase 6 pandemic.

            It is as necessary now to be seeking ways to prognosticate the outcome as it was 2 years ago. We are smart, thinking humans. We have the capacity to figure this out.

            Comment


            • #51
              Re: G143R N186K Q196R S227N

              Originally posted by niman
              The key players (using H3 numbering) are G143R, N186R, Q196R, S227N.
              I keep returning to this thread, and in particular this post. It seems that this sums it up succinctly. Any further recombination in a mammalian resevoir will pick the lock. It really appears to be on the cusp of pandemic. The slow train wreck is coming into the station IMHO.
              21st Century Omega Man

              Comment


              • #52
                Re: G143R N186K Q196R S227N

                Originally Posted by niman
                The key players (using H3 numbering) are G143R, N186R, Q196R, S227N.


                could someone explain these numbers too me in laymans terms please.??.

                Comment


                • #53
                  Re: G143R N186K Q196R S227N

                  vinny, theses numbers represent the location & the kind of change the genetic code must do in the virus physical structure to allow a human-to-human transmission, may it be effective of not.

                  Comment


                  • #54
                    Re: G143R N186K Q196R S227N

                    Originally posted by vinny
                    Originally Posted by niman
                    The key players (using H3 numbering) are G143R, N186R, Q196R, S227N.


                    could someone explain these numbers too me in laymans terms please.??.
                    The abreviations show the position in the protein (in this case HA) and how it has chnaged. S227N means the S (serine) that is usually found at position 227 has been replaced by N (aspagine). This change was predicted because the H5N1 flying into the Middle East could combine with the H9N2 sequences in poultry.

                    This travel log shows that the two isolates in Turkey and the one isolate in Egypt have the predicted sequence, which is shared with the S227N positive H5N1 sequences from Hong Kong, as well as the H9N2 sequences in the Middle East.

                    Thus, the only matching sequences are those predicted in October 22, 2005

                    http://www.recombinomics.com/News/10...mbination.html

                    Efficient Human to Human Transmission Via H5N1 / H9N2 Recombination

                    Recombinomics Commentary

                    October 22, 2005

                    In the upcoming Virology paper "Evolution of the receptor binding phenotype of influenza A (H5) viruses, Gambaryan et al screen H5 isolates for affinity for human Sia2-6Gal (human-like) receptors. Two isolates, A/Hong Kong/212/2003 and A/Hong Kong/213/2003 were identified. Both isolates had the S227N polymorphism.


                    EF042617 A/Egypt/2947-NAMRU3/2006 HA (4) 1596 2006 H5N1
                    ISDN133098 A/Turkey/12/2006 HA (4) 1659 2006 H5N1
                    ISDN133364 A/Turkey/65596/06 HA (4) 1659 2006 H5N1
                    AY575869 A/Hong Kong/212/03 HA (4) 1664 2003 H5N1
                    AB212054 A/Hong Kong/213/03 HA (4) 1779 2003 H5N1
                    ISDN38262 A/Hong Kong/213/2003 HA (4) 1750 2003 H5N1
                    AY575870 A/Hong Kong/213/2003 HA (4) 1593 2003 H5N1
                    AY738456 A/ostrich/Eshkol/1436/03 HA (4) 1707 2003 H9N2
                    DQ104453 A/turkey/Avigdor/1209/03 HA (4) 438 2003 H9N2
                    DQ104454 A/turkey/Avigdor/1215/03 HA (4) 438 2003 H9N2
                    DQ104458 A/turkey/Brosh/1276/03 HA (4) 438 2003 H9N2
                    DQ104455 A/turkey/Kfar Warburg/1224/03 HA (4) 438 2003 H9N2
                    DQ104464 A/chicken/Kfar Monash/636/02 HA (4) 438 2002 H9N2
                    DQ104450 A/turkey/Avichail/1075/02 HA (4) 864 2002 H9N2
                    DQ104473 A/turkey/Beit HaLevi/1009/02 HA (4) 438 2002 H9N2
                    DQ104451 A/turkey/Ein Tzurim/1172/02 HA (4) 438 2002 H9N2
                    DQ104462 A/turkey/Givat Haim/622/02 HA (4) 864 2002 H9N2
                    DQ104471 A/turkey/Givat Haim/868/02 HA (4) 858 2002 H9N2
                    AY548507 A/turkey/Givat Haim/965/02 HA (4) 438 2002 H9N2
                    AY738452 A/turkey/Givat Haim/965/02 HA (4) 1707 2002 H9
                    AY548510 A/turkey/Kfar Vitkin/615/02 HA (4) 438 2002 H9N2
                    DQ104459 A/turkey/Kfar Vitkin/615/02 HA (4) 867 2002 H9
                    DQ104460 A/turkey/Kfar Vitkin/616/02 HA (4) 867 2002 H9
                    AY548511 A/turkey/Kfar Vitkin/616/02 HA (4) 438 2002 H9N2
                    AY548512 A/turkey/Mishmar Hasharon/619/02 HA (4) 438 2002 H9N2
                    DQ104461 A/turkey/Mishmar Hasharon/619/02 HA (4) 864 2002 H9
                    DQ104449 A/turkey/Naharia/1013/02 HA (4) 438 2002 H9N2
                    DQ104452 A/turkey/Sapir/1199/02 HA (4) 438 2002 H9N2
                    AY548513 A/turkey/Yedidia/625/02 HA (4) 438 2002 H9N2
                    DQ104463 A/turkey/Yedidia/625/02 HA (4) 855 2002 H9
                    DQ104448 A/turkey/Yedidia/911/02 HA (4) 867 2002 H9N2
                    AY548514 A/chicken/Tel Adashim/786/01 HA (4) 438 2001 H9N2
                    AY738454 A/chicken/Tel Adashim/786/01 HA (4) 1707 2001 H9
                    DQ104465 A/chicken/Tel Adashim/809/01 HA (4) 864 2001 H9
                    AY548515 A/chicken/Tel Adashim/809/01 HA (4) 438 2001 H9N2
                    AY548500 A/chicken/Tel Adashim/811/01 HA (4) 438 2001 H9N2
                    DQ104467 A/chicken/Tel Adashim/811/01 HA (4) 868 2001 H9
                    DQ104468 A/chicken/Tel Adashim/812/01 HA (4) 867 2001 H9
                    AY548501 A/chicken/Tel Adashim/812/01 HA (4) 438 2001 H9N2
                    DQ104469 A/goose/Tel Adashim/829/01 HA (4) 438 2001 H9N2
                    DQ104470 A/goose/Tel Adashim/830/01 HA (4) 438 2001 H9N2
                    DQ104466 A/turkey/Givat Haim/810/01 HA (4) 855 2001 H9
                    AY548499 A/turkey/Givat Haim/810/01 HA (4) 438 2001 H9N2
                    DQ104472 A/chicken/Maale HaHamisha/90658/00 HA (4) 438 2000 H9N2
                    AY738451 A/turkey/Neve Ilan/90710/00 HA (4) 1707 2000 H9
                    AY548502 A/turkey/Neve Ilan/90710/00 HA (4) 438 2000 H9N2
                    AF218108 A/Peking Duck/Malaysia/F20/1/98 HA (4) 464 1998 H9N2
                    CY005925 A/mallard/Alberta/52/1997 HA (4) 1737 1997 H12N5
                    AF218105 A/Peking Duck/Singapore/F91-5/9/97 HA (4) 464 1997 H9N2
                    AY206675 A/quail/Hong Kong/A28945/88 HA (4) 1683 1988 H9N2

                    Comment


                    • #55
                      Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

                      Commentary at

                      http://www.recombinomics.com/News/11...ding_Post.html

                      Comment


                      • #56
                        Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

                        Thank you Dr. Niman for pointing out, once again, the importance of releasing sequence data.

                        from: http://www.recombinomics.com/News/11...ding_Post.html

                        Commentary

                        Post Publication Hoarding of H5N1 Sequences by The WHO
                        Recombinomics Commentary
                        November 21, 2006

                        Most journals now expect that DNA and amino acid sequences that appear in articles will be submitted to a sequence database before publication.

                        The above instructions to submitters of sequences to Genbank reflect the requirements for most major peer reviewed journals. The underlying premise of peer review publications require authors to include information needed for independent confirmation of the results being published.

                        In the past, WHO and consultants have withheld H5N1 sequences until publication. This hoarding of data prevents independent analysis of a rapidly evolving H5N1 genome. Such hoarding is curious, since the hoarders frequently receive samples for independent confirmation of H5N1 per WHO requirements. Thus, although the samples are collected by public health agencies, the data is withheld from the public by the WHO affiliated labs until publication.

                        However, the sequence hoarders have now extended the hoarding beyond publication. This has been done in two recent high profile publications.

                        One publication, in the Proceedings of the National Academy of Science (PNAS) on the spread of the Fujian strain of H5N1 in southern China, has sparked considerable controversy and requests by the WHO for China to release more H5N1 samples and sequences.

                        The second publication, in Nature, focused on changes in the receptor binding domain that increased affinity for human receptors. Both papers were heavily dependent on sequence data, and both papers use data that is being hoarded the the WHO private database.

                        The private database has thousands of withheld H5N1 sequences. One of the largest hoarders has been Weybridge, which received H5N1 samples from birds, mammals, and humans collected throughout Europe and the Middle East during last seasons H5N1 outbreak.

                        Sequences from one bird in Turkey, four patients in Turkey, and one patient in Azerbaijan have been released in the past few months. However, a presentation of the spread of H5N1 in Europe in 2006 included phylogenetic trees (here and here), which contain approximately 80 HA Qinghai sequences that had been completed by the presentation date, May 30, 2006. Since there are 8 gene segments per isolate, and the presentation did not included human isolates, it is likely that well over 1000 sequences are currently being hoarded by Weybridge, even though many samples were colelcted over a year ago, and otehrs were from the beginning of 2006.

                        The sequences in the PNAS paper were from 406 H5N1 isolate collected in southern China in 2005 and 2006. 406 isolates would generated 3248 gene sequences, but only 556 were released (404 full or partial HA sequences and 152 PB2 sequences). The paper discussed the genotypes of the isolates, which require sequence data for all eight gene segments from each isoalte. The paper also discussed amantadine resistance, which is based on the sequence of the M2 gene. The paper included accession numbers for the 556 sequences described above. There were no sequences released for six gene segments (PB1, PA, NP, NA, MP, NS).

                        The Nature paper described receptor binding domain changes in various H5N1 isolates from Vietnam and Thailand patients. Although the paper included the amino acid changes of the southeast Asian clones, the nucleic acids sequences from these clones were withheld. The paper repeatedly states that these changes were "mutations", but fails to provide sequence data that would include the silent changes in the RNA, which would contain data relevant to the "mutation" claim.

                        One of the changes discussed in the paper was S227N, which was found in one of the clones from a patient from Vietnam. This change had been predicted based on recombination, and the prediction on the precise nucleotide change was made prior to the detection of such changes in Turkey and Egypt. These isolates had the predicted nucleotide change, which was confirmed by the nucleotide sequences deposited by others at GenBank. The precise change could not be determined from the protein sequence, because of the redundancy in the genetic code. The change in the Vietnamese clone, or an earlier isolate,
                        A/VN/JP12-2/05, from another Vietnam patient can not be determined, because these sequences are being hoarded by WHO in its private database, even though papers on both sequences have now been published (the earlier isolate was published by the WHO Global Influenza Surveillance Network in Emerging Infectious Diseases).

                        In addition, the Nature paper cited detection of N186K and Q196R in Qinghai H5N1 isolates from patients in Azerbaijan and Iraq. These changes could not be confirmed, because sequences from these patients are also being hoarded in the WHO database.

                        Thus, the WHO is currently hoarding more H5N1 sequences than any agency, yet it requests samples and sequences from China, because of the importance of such sequences in the monitoring of the evolution of H5N1, which is required for the creation of updated diagnostic primers, as well as new vaccine targets.

                        WHO consultants have expressed the view that such vaccine targets could not predicted because the changes in H5N1 are due to random mutations. However, the public H5N1 sequences, as well as other influenza serotypes, have clear examples of recombination, which create new gene sequences by using previously identified changes. Similarly, the single nucleotide changes, which are considered as point mutations by the WHO consultants, can also be readily identified in reported sequences, including H5N1 sequences that are likely to be involved in dual infections via transport and transmission by wild birds.

                        As the sequence data accumulations, the "random mutation" explanations becomes less tenable. The NIAID has a flu sequencing project which will generate full sequences at no cost, yet the H5N1 sequences database is littered with partial sequences from published H5N1 collected since 1999. The generation and release of full sequences from these isolates would provide a more complete evolution of H5N1 and provide more examples of obvious recombination.

                        The hoarding of the sequences by WHO and consultants continue to be hazardous to the world's health.

                        The post-publication hoarding has set a new transparency low.
                        "In the beginning of change, the patriot is a scarce man (or woman https://flutrackers.com/forum/core/i...ilies/wink.png), and brave, and hated and scorned. When his cause succeeds, the timid join him, for it then costs nothing to be a patriot."- Mark TwainReason obeys itself; and ignorance submits to whatever is dictated to it. -Thomas Paine

                        Comment


                        • #57
                          Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

                          Henry- wow, that was a well thought out and well presented commentary. Pretty crystal clear. Thanks for staying the course and keeping the bell ringing. Yours is one of the voices that has influened the releases so far, I beleive it's work like this commentary that may influence improved sequence availability.

                          Thank you.
                          Upon this gifted age, in its dark hour,
                          Rains from the sky a meteoric shower
                          Of facts....They lie unquestioned, uncombined.
                          Wisdom enough to leech us of our ill
                          Is daily spun, but there exists no loom
                          To weave it into fabric..
                          Edna St. Vincent Millay "Huntsman, What Quarry"
                          All my posts to this forum are for fair use and educational purposes only.

                          Comment


                          • #58
                            Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

                            Regarding unnecessary hoarding, I'm continually surprised at the short sightedness of some scientists. Are they so convinced that they can develop a successful life-saving VAX from the hoarded information, that it is not necessary to have all minds working on this issue? We constantly hear how there is no VAX because they don't know what the deadly pandemic version will be, yet they deny others the opportunity to help remedy that situation.......it's simply not logical. How can the public have confidence in the success of their work with this continued illogical reasoning?

                            When someone calls 911, does the dispatch operator take their "hoarded" maps and go help the person? No....they broadcast that information, the location, and the directions on how to get there. Any and all officers near the location go help - NOT the dispatcher with the only map.

                            I consider this emergency an extraordinary 911 call and I expect all available scientists to come to the aid of those in danger.

                            .
                            "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


                            • #59
                              Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

                              THANK YOU, DR. NIMAN, FOR YOUR IMMENSE COURAGE!

                              In War, ultimately it is not bullets and bombs that kill thousands of people, but pride on the part of the principle players.

                              Too proud to negotiate.
                              Too proud to admit error.
                              Too proud to share power with others.

                              We face a viral War against the human race; pride and turf wars are preventing the building of a solid defense.

                              The problem lies in us, in our human nature.

                              4-ABBA

                              Comment


                              • #60
                                Re: Nature - HA mutations responsible for the binding of H5N1 A viruses

                                Originally posted by 4-ABBA

                                We face a viral War against the human race; pride and turf wars are preventing the building of a solid defense.


                                4-ABBA
                                May I add...there will be no winners - we will all lose someone/something in this "war". Scientists have tremendous power right now. Like so many others, I call on them to take a stand and use their power for the good of all humanity.
                                "In the beginning of change, the patriot is a scarce man (or woman https://flutrackers.com/forum/core/i...ilies/wink.png), and brave, and hated and scorned. When his cause succeeds, the timid join him, for it then costs nothing to be a patriot."- Mark TwainReason obeys itself; and ignorance submits to whatever is dictated to it. -Thomas Paine

                                Comment

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