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  • Spread and Evolution of Tamiflu Resistance H274Y

    <big><big>Commentary
    </big></big>
    Concurrent Acquisition of H274Y Tamiflu Resistance in Japan
    Recombinomics Commentary 19:00
    July 11, 2008

    The preliminary analysis suggests that the resistant mutants do not share a single origin and further genotypic analysis is ongoing.

    The above comment from the last WHO update entitled "Influenza A(H1N1) virus resistance to oseltamivir" confirms the analysis of public H1N1 sequences as well as the sequences represented on the NA phylogenetic tree of recent isolates from Japan.

    The sudden appearance of oseltamivir resistance worldwide has startled influenza "experts" because the appearance was sudden and not linked to oseltamivir treatment of seasonal flu. The resistance was limited to one position, H274Y, on H1N1, which is the same dominant change in H5N1. This change first began to appear in public sequences from the 2006/2007 season in isolates from the United States. Those isolates were from the New Caledonia strain, and similar results were not reported elsewhere, although sequences from the United States make up the vast majority of public NA sequences.

    However, early this year Norway reported H274Y levels exceeding 50% of H1N1 NA sequences, which sounded alarm bells worldwide, in part because oseltamivir was a front line anti-viral commonly used to treat H5N1 patients and also to be used as a blanket to prophylacticly treat wide areas with confirmed H5N1. H274Y was subsequently reported in H5N1 infected wild birds, which was then followed by the increase in H274Y in the 2006/2007 season, and the explosion of cases in the 2007/2008 season.

    Analysis of public sequences from the United States indicated that the New Caledonia strain of 2006/2007 was replaced by the Solomon Island/3 and Brisbane/59 strains in 2007/2008. The H274Y in the US in the most recent season was limited to the Brisbane strain, but the analysis of the sequences identified three independent introductions. The largest group was found throughout the United States and matched sequences from England and Turkey. The latest data from Japan indicates it also is closely related to sequences from Norway, France, and Japan. These isolates could all come from a common introduction and are shaded and labeled "Northern EU-like" in the phylogram from Japan.

    However, in the United States, two isolates from Hawaii were one a separate branch, with additional isolates from Hawaii and California which did not have H274Y, indicating the Hawaiian samples, which are listed in the phylogram and labeled "Hawaii-like". However, the branch with the two positives from Hawaii also has an isolate from Miyagi once again showing that the acquisition of H274Y was an independent event that happened after this branch was formed. Similarly, seven additional isolates from Japan form a closely related branch, but only four of the seven isolates on that branch have H274Y. Similarly another closely related branch have five isolate that have H274Y. The isolates from Yokohama are epidemiologically linked but they are also related to an isolates from Yamagata, which also doesn't have H274Y, again indicating that these branches represent additional introductions.

    Similarly, in the United States, a recent isolate from Florida is on teh same seperate branch with other isoaltes from Florida, but only one of the three Florida sequences has H274Y.

    The phylogenetic tree from Japan has additional examples of H274Y mapping to more branches, which contain isolates without H274Y, again indicating that the H274Y isolates on those branches have also acquired H274Y independently.

    This simultaneous acquisitions of the same polymorphisms onto multiple genetic backgrounds is similar to the results described for another NA polymorphisms, G743A, found on multiple clade 2.2 H5N1 genetic backgrounds. These acquisitions also appeared concurrently on multiple genetic backgrounds found in divergent locations, which can be most easily explain by recombination with a common source.

    Thus, the acquisition of H274Y onto multiple genetic backgrounds provides additional support for acquisition via recombination from a common source. In the case of H274Y, the initial acquisition may have come from H5N1 in 2006/2007, but the explosion of cases this season is likely due to movement of H274Y from one Brisbane/59 genetic background to another as was seen in the case of G743A on clade 2.2 genetic backgrounds.





  • #2
    Re: Concurrent Acquisition of H274Y Tamiflu Resistance in Japan

    <big><big>Commentary
    </big></big>
    H274Y Tamiflu Resistance Explodes in Tottori Japan
    Recombinomics Commentary 22:15
    July 11, 2008

    According to the preliminary report from a local health laboratory, oseltamivir resistance prevalence have been dramatically increasing in Tottori prefecture located at west of the main island of Japan (30% of total isolates in the prefecture, analysis in detail is ongoing).

    The above comments are from Japan?s recent update on H274Y in H1N1 seasonal flu. Although overall, the incidence of H274Y in H1N1 isolates was only 1.6%, as noted above the Tamiflu resistance frequency is exploding in Tottori. In addition to a description of many of the resistant cases, the report has an NA phylogenetic tree of the isolates from Japan along with several of the public sequences from the United States and England.

    The largest group outside of Japan is listed as ?Northern EU-like? and this version of H5N1 has also reached Japan (in isoaltes from Yokohama). However, the tree has four of the isolates from Tottori, which map onto two branches which are distinct from the large branch which also has isolates from the United States, France, and England.

    One of the branches with 2008 Tottori isolates (numbers 28 and 29) also has A/Washington/28/07, which is a public sequences that is closely related to other isolates from the state of Washington (33, 34, and 40). None of these four closely related isolates from the state of Washington have H274Y, but both isolates from Tottori do, indicating the H274Y was acquired after this set of isolates formed a separate branch. Thus, the acquisition of H274Y by these two Tottori isolates was independent of the isolates in the larger ?Northern EU? group.

    Similarly, the other two Tottori isolates (numbers 23 and 21) fall onto another branch which include other public sequences from the United States. The upper portion of this branch include two H274Y isolates from Hawaii (21 and 28), but the upper branch has other isolates that do not have H274Y, as seen in the tree from Japan (Hawaii/31/07 and Miyagi23/08). Other public sequences also map to the upper portion of this branch (Hawaii/35/07, Hawaii/18/07, California/28/07), indicating the two positives from Hawaii are distinct from the positives listed above.

    Moreover, on the lower portion of the branch, which has the two isolates from Tottori, are other isolates from Japan that are negative for H274Y (Shiman/7/08, Yamaguchi/14/08, Kyoto-C/1/08) along with two isolates that are positive (Gifu-C/17/08 and Gifu-C/38/08), indicating these isolates are also due to introductions that are independent of the isolates above.

    The acquisition of the same polymorphisms onto different genetic backgrounds circulating in the same geographical area is similar to H5N1 data for poultry in the Nile Delta. In those cases distinct genetic backgrounds acquired the same change (G743A) at the same time, which was supported by related sequences which did not acquire the change. Thus, the same change among a small number of acquistions cannopt be easily explained by a "random mutation" mechanism.

    Attempts to explain these acquisitions via the current basic tenet from influenza drift, selection of random mutations, is difficult. The H5N1 examples involved a synonymous change. Similarly the sudden appearance of H274Y has appeared on multiple genetic backgrounds in patients who were not taking Tamiflu.

    Consequently, influenza ?experts? have been startled by the sudden appearance of Tamilu throughout the world on multiple Brisbane/59 genetic backgrounds. However, these acquisitions are readily explained by recombination between closely related sequences, such as those defined above.

    These concurrent acquisitions of single nucleotide polymorphisms continue to raise serious doubt about the roll of de novo mutations in the creation of antigenic or genetic drift.




    Comment


    • #3
      Re: Concurrent Acquisition of Tamiflu Resistance H274Y

      <big><big>Commentary
      </big></big>
      Global Expansion of H274Y Tamiflu Resistance
      Recombinomics Commentary 16:42
      July 12, 2008

      The recent release of phylogenetic trees with 2008 NA sequences with H274Y has allowed for more detailed analysis. Previously, analysis was possible using public NA sequences, which were almost exclusively sequences from the United States generated by the CDC. There was also one full sequence from England, as well as partial sequences from Turkey and Hong Kong.

      The public sequences contained H274Y in sequences from five individual infected during the 2006/2007 season inI the United States. All five were infected with the H1N1 New Caledonia/20 strain. Previously, no H1N1 public sequence contained H274Y.

      The level of H274Y increased markedly in the 2007/2008 season. Initial reports came from Norway, where more than 50% of H1N1 isolates had H274Y. In the United States, the number of isolate also jumped, and all isolates were the emerging Bisbane/59 strain. Thus the over-all rate in the US was only 10% of H1N1, but the H1N1 infections in the US included Solomon Island/3 isolates, which did not have H274Y.

      However, the data in the US indicated there were at least three separate introductions. The largest sub-clade was found throughout the country and accounted for the vast majority of isolates. However, two isolates in Hawaii mapped to a branch with other isolates from Hawaii and California. However, since of two isolates had H274Y, that introduction was after that branch formed.

      Similarly, a 2008 isolate from Florida with H274Y fell onto a branch with 2007 isolates from Florida, which did not have H274Y, indicating the Florida case was a third independent introduction.

      The recent release of a phylogenetic tree from Japan indicated there were many independent introductions there, even though most of the H274Y positive patients did not take Tamiflu in the two weeks prior to samples collection. Only 2 of the 22 H274Y patients were known to have take Tamiflu (and the Tamiflu status of four additional patients was unknown). Thus, like the H274Y patients in other countries, the presence of H274Y was not linked to Tamiflu usage.

      The phylogram from Japan included several of the isolates from the US, as did other phylograms by others, such as slide 9, slide 6, and slide 24 On the phylogram from Japan, the branch labeled ?Northern EU-like? has a series of isolates which have H274Y. Analysis of the other phylograms creates a list of isolates which match to this large branch, which are listed below. This list includes isolates from Norway, the United States, Canada, Russia, Japan, and Trindad indicating this subclade is widespread and present in the countries with the highest incidence of H274Y. Since all isolates on this branch have H274Y, they could have had a common origin.

      However, the Hawaii and Florida isolates described above fall on lower branches, as do isolates from Japan (see second list below). These isolates on the phylogram from Japan represent multiple independent introductions. Similarly isolates from the other phylograms indicate there are additional introductions in France, Greece, and Thailand signaling new introductions of H274Y onto multiple Brisbane/59 genetic backgrounds (clade 2B).

      Thus, the global expansion of H274Y is dependent of the spread of the Northern-EU-like strain, but is also spreading via a series on new introductions onto multiple genetic backgrounds with are also clade 2B, but distinct from the isolates in the countries with the highest levels of H274Y.

      This global expansion is almost certainly due to the acquisition of these other sub-clades via recombination with Northern EU-like sequences. These sequences are closely related and differ by a single amino acid at the protein level, although there are many additional differences at the nucleotide level. Thus, these synonymous changes generate the new branches on the phylogenetic trees, but these isolate are antigenically close.

      This acquisition of H274Y onto multiple closely related genetic backgrounds, is similar to G743A concurrent acquisitions onto NA in H5N1 isolates. Like the H274Y example above, the global expansion was sudden and involved a large number of similar (clade 2.2) but distinct genetic backgrounds, which mapped to branches that included isolates without the acquisition.

      This type of expansion of a signal nucleotide polymorphism is most easily explained by homologous recombination with a common source, which leads to sudden and dramatic expansion of a given polymorphisms onto multiple genetic backgrounds.

      For H274Y, the expansion has serious implications for use of Tamiflu to control a pandemic H5N1. H274Y is also the major Tamiflu resistance change on N1 in H5N1, so an efficiently transmissible H5N1 could easily infect H1N1 positive people, leading to Tamiflu resistance on H5N1, even in the absence of Tamiflu usage.

      Thus, even though H274Y on seasonal flu does not lead to changes in the clinical course, the dramatic increase in the N1 pool of H274Y raises serious pandemic concerns.

      Northern EU-like isolates with H274Y

      Arizona/03/07
      Arizona/13/07
      Arizona/14/07
      Arizona/15/07
      British Columbia/RV1585/07
      England/557/07
      Illinois/10/07
      Sydney/142/07
      Sydney/143/07
      Sydney/144/07

      Maryland/04/07
      New Jersey/15/07
      New Jersey/16/07
      New Jersey/20/07
      Norway/1630/07
      Norway/1651/07
      Norway/1684/07
      Norway/1687/07
      Norway/1701/07
      Norway/1731/07
      Norway/1736/07
      Norway/1743/07
      Norway/1745/07
      Norway/1747/07
      Ontario/RV0131/2007
      Paris/0577/07
      Paris/0644/07

      Hawaii/01/08
      Hawaii/02/08
      Indiana/01/08
      Lisbon/3/08
      Memphis/3/08
      Minnesota/1/08
      New Jersey/05/08
      New Jersey/06/08
      New Jersey/10/08
      North Carolina/2/08
      Pennsylvania/02/08
      St Petersburg/16/2008
      Trinadad/14/2008
      Washington/01/08
      Wisconsin/01/08
      Yokohama/77/08
      Yokohama/78/08
      Yokohama/79/08

      "Hawaii" like isolates with H274Y

      Hawaii/21/07
      Hawaii/28/07
      Lyon/1337/07
      Thailand/1577/2007

      Aichi/76/08
      Athens/41/2008
      Florida/2/08
      Gifu-C/17/08
      Gifu-C/38/08
      Kobe/27/08
      Shimane/59/08
      Tochigi/8/08
      Tochigi/34/08
      Tochigi/39/08
      Tottori/21/08
      Tottori/23/08
      Tottori/28/08
      Tottori/29/08
      Volos/108/2008
      Yamagata/68/08
      Yokohama/22/08
      Yokohama/30/08
      Yokohama/31/08
      Yokohama/34/08
      Yokohama/35/08




      Comment


      • #4
        Re: Concurrent Acquisition of Tamiflu Resistance H274Y

        "Yamagata, which also doesn't have H274"

        There are several Yamagata quasi-strains, some with H274, others having another polymorphism conferring tamiflu resistance, correct?

        So does this parallel Hawaii isolates that also do/don't have H274? The Japanese are among the largest ethnic subpop in Hawaii and are also the most frequent foreign visitors. So there is zero surprise to see repeated pattern, even though they map to separate branches.

        Comment


        • #5
          Re: Concurrent Acquisition of Tamiflu Resistance H274Y

          Originally posted by Oracle View Post
          "Yamagata, which also doesn't have H274"

          There are several Yamagata quasi-strains, some with H274, others having another polymorphism conferring tamiflu resistance, correct?

          So does this parallel Hawaii isolates that also do/don't have H274? The Japanese are among the largest ethnic subpop in Hawaii and are also the most frequent foreign visitors. So there is zero surprise to see repeated pattern, even though they map to separate branches.
          Yes, the two Hawaiian isolates that have H274Y are on a branch with isolates from Hawaii and California that don't have H274Y.

          Comment


          • #6
            Re: Concurrent Acquisition of Tamiflu Resistance H274Y

            Evolution of H274Y Tamiflu Resistance Baffles Experts
            Recombinomics Commentary 23:55
            July 13, 2008

            The preliminary analysis suggests that the resistant mutants do not share a single origin and further genotypic analysis is ongoing.

            The above comment from the WHO update entitled "Influenza A (H1N1) virus resistance to oseltamivir" is confirmed by a multitude of phylogenetic trees of recent H1N1 isolates from a number of countries, which can be analyzed in conjunction with public sequences. These sequences contain H274Y, which confers Tamiflu resistance. The sudden appearance of Tamiflu resistance in seasonal flu linked to independent introductions of H274Y into populations that rarely use Tamiflu has startled and baffled influenza ?experts? who expect such antigenic drift to be linked to selection of random mutations. However, the explosion of Tamiflu resistance in seasonal flu is just one of many surprises associated with this change, which is chronicled below.

            H274Y gained considerable attention when it appeared in Tamiflu treated H5N1 patients in Vietnam in 2005. H5N1 was linked to an explosion of human cases in Vietnam and Thailand in 2004 and the H5N1 was classified as clade 1, in contrast to clade 2 H5N1 in birds which had emerged in China and multiple countries to the east of China. Clade 1 was a concern because it was quite different from the earlier H5N1 outbreaks in humans and stockpiled vaccines were a poor match. Moreover, all clade 1 isolates had two amantadine resistance markers in the M2 protein, so the only anti-virals of choice with the neuraminidase inhibitors. However, Relenza was not available in quantity, so the drug of choice was Tamiflu (osletamivir).

            However, earlier data on use of Tamiflu against the nine neuraminidase serotypes indicate N1 was one of the serotypes with the highest level of resistance. Moreover, inhibition testing of H5N1 from Vietnam required an even higher level of Tamiflu to achieve a 50% marker, indicating treatment dose levels were near the limits of efficacy. Use was compromised further because Tamiflu was most effective when administered with 48 hours of disease onset, and in most cases treatment would begin many days after disease onset because H5N1 infections initial present with many of the same symptoms as seasonal flu, which is not traditionally treated with anti-virals in southeast Asia.

            However, Tamiflu was the only real anti-viral choice, so it was used to treat and prevent H5N1. The prophylactic dose was half of the treatment dose, raising additional concerns of resistance due to sub-optimal treatment, but its use was implemented in a plan to blanket H5N1 regions with Tamilfu, to blunt and initial human transmission.

            In 2005, Tamiflu resistance was identified in H5N1 patients being treated with Tamiflu, as well as one contact who was receiving a prophylactic dose because her brother was hospitalized and H5N1 positive. H274Y was identified in patients being treated as well as the patient being treated initially with a prophylactic dose. Moreover, the prophylactic patient had H5N1 with a second Tamiflu resistance change N294S. Moreover, H274Y was also detected in a member of the Karo cluster in Indonesia who had prematurely stopped taking Tamiflu. In Indonesia, the H5N1 was clade 2.1.

            However, assurances were given that the resistance markers, especially H274Y, was associated with a fitness penalty, so although the resistance would cause problems in infected patients, it would only be viable in patients that were being treated with Tamiflu, because H274Y would reduce the ability of H5N1 to compete with wild type H5N1. However, the fitness penalty was previously reported in seasonal flu, and the applicability to H5N1 was unclear.

            There were several pieces of data that raised concerns about assurances based on a fitness penalty. Both H274Y and N294S had been previously been reported in poultry suggesting that H5N1 with either mutation could compete with wild type H5N1. Additional concerns were linked to a cluster of H5N1 cases in Egypt, which had N294S in samples collected prior to Tamiflu treatment. Moreover, H274Y was detected in wild bird isolates in Astrakhan, raising additional doubts about a fitness penalty. The H5N1 in the above instances was clade 2.2 extending the number of different H5N1 clades and sub-clades with H274Y or N294S.

            Concerns that the Tamiflu resistance could be acquired by seasonal flu began shortly thereafter in the 2006/2007 season, when five N1 sequences with H274Y became public. All five H1N1 infected patients were from the United States, but these five sequences represented less than 1% of N1 sequences that season, so the significance was unclear, although H274Y was not reported for any prior human H1N1 public sequence.

            Concerns grew markedly the followings season, when Norway reported that more than half of the H1N1 infections contained H274Y. These concerns increased when H1N1 sequences from the United States were released. Approximately 30% of the Brisbane/59 (clade 2B) had H274Y, and there were at least independent introductions. Recently phylogenetic trees identify an number of additional introductions in isolates from patients in Japan which had not been treated with Tamiflu prior to sample collection. The data from other countries indicated the H274Y was concentrated in clade 2B, and the frequencies were increasing in multiple countries.

            This global spread of H274Y through introductions onto multiple gentic backgrounds indicated the H274Y was not spreading via selection of random mutations, but instead was being acquired by homologous recombination as was previously described for G743A in H5N1.

            The data support the concurrent acquisition of the same polymorphism onto multiple genetic backgrounds and suggest Tamiflu will have limited utility in the treatment of prevention a pandemic linked to efficient transmission of H5N1.




            Comment


            • #7
              Re: Evolution of Tamiflu Resistance H274Y

              Commentary

              Emergence of H1N1 Relenza Resistance In Pennsylvania
              Recombinomics Commentary 14:48
              July 17, 2008

              The recent explosion of H1N1 Tamiflu (oseltamivir) resistance worldwide has focused attention on the other neuraminidase inhibitor, Relenza (zanamivir). Recently deposited H1N1 sequences from Asia had a novel polymorphism, Q137K, which confer resistance to Relenza (see list below).

              A recently released NA sequences from Pennsylvania, A/Pennsylvania/01/2008, contains a mixture which encodes for both Q136 and Q136K. Like the more recent isolates from Asia, this isolate is on a clade 2B (Brisbane) background. In contrast, the earlier isolates were on a clade 2A (Solomon Islands) background.

              Moreover, the introductions onto each background were independent suggesting that the Q136K polymorphism is spreading among H1N1 backgrounds by the same mechanism that is spreading the Tamiflu resistance H274Y onto multiple genetic backgrounds.

              Like the spread of G743A on clade 2.2 backgrounds, this sudden and concurrent spread of the same polymorphism onto multiple genetic backgrounds is most easily explained by homologous recombination.

              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

              http://www.recombinomics.com/News/07.../Q136K_PA.html

              http://www.flutrackers.com/forum/showthread.php?t=74429
              Last edited by AlaskaDenise; July 22, 2008, 01:23 PM. Reason: replaced commentary with corrected version from source - per Niman

              Comment


              • #8
                Re: Evolution of Tamiflu Resistance H274Y

                <big><big>Commentary
                </big></big>
                Emergence of H1N1 Tamiflu Resistance on Clade 2C In China
                Recombinomics Commentary 13:53
                July 17, 2008

                NA sequences being released at Genbank include two isolates from China with H274Y. The isolates (A/Zhejiang/Xiangshan522/2006 and A/Gansu/Chenguan/1129/2007) were collected in the 2006/2007 season in August and January, and are related to A/Hong Kong/2652/2006, the prototype clade 2C sequence which is widely circulating in Asia. All three of the above isolates, like the vast majority of clade 2C isolates, has M2 S31N, conferring amantadine resistance.

                The presence of H274Y in China in clade 2C has not been reported previously. Moreover, the upcoming paper ?Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide in 2004-2008? indicated that these patients did not develop the resistance due to Tamiflu treatment. In the 2006/2007 season, public sequences with H274Y were limited to New Caledonia, clade 1 in five isolates in the United States. Four of these isolates were described in the above paper, and only one of the four had been treated with Tamiflu prior to sample collection. In the 2007/2008 the incidence of H274Y exploded in the Brisbane/59 strain, clade 2B and almost all patients positive for H274Y had not been treated with Tamiflu prior to sample collection.

                Thus, in the past two seasons, H274Y has been reported on clade 1, 2B, and 2C genetic backgrounds. Moreover, phylogenetic analysis of clade B isolates indicates the H274Y was due to multiple independent introductions.

                These independent introductions onto multiple genetic backgrounds which are clustered in time are similar to G743A introductions in H5N1 in early 2007 on a varient of clade 2.2 genetic backgrounds.

                These data are most easily explained by homologous recombination with a common source.




                Comment


                • #9
                  Re: Evolution of Tamiflu Resistance H274Y

                  <big><big>Commentary
                  </big></big>
                  Vaccine Mismatch Drives H1N1 Tamiflu Resistance
                  Recombinomics Commentary 23:59
                  July 17, 2008

                  A total of 200 (69%) of 290 influenza A (H1N1) viruses were characterized as A/Solomon Islands/3/2006-like, the influenza A (H1N1) component of the 2007--08 influenza vaccine for the Northern Hemisphere, and 70 (24%) were characterized as A/Brisbane/59/2007-like, the recommended H1N1 component of the 2008--09 Northern Hemisphere vaccine.

                  All the oseltamivir-resistant viruses have been influenza A (H1N1) viruses and have been determined to share the same genetic mutation that confers oseltamivir resistance. These 84 viruses represent 10.2% of the 824 influenza A (H1N1) viruses that have been tested, an increase from four (0.7%) of 588 influenza A (H1N1) viruses tested during the 2006--07 season.

                  The majority of influenza A (H1N1) viruses were characterized as A/Solomon Islands/3/2006, the influenza A (H1N1) component of the 2007--08 influenza vaccine for the Northern Hemisphere.

                  The above comments from the CDC MMWR report on the 2007/2008 seasonal influenza in the United States is not supported the by the HA and NA sequences from approximately 150 influenza isolates from the 2007/2008 season released by the CDC. Similarly, the data from the phylogenetic analysis also fails to support the above comments.

                  The public data from the CDC indicates all of the reported H1N1 isolates in the 2007/2008 season were either Brisbane/59/2007-like (clade 2B) or Hong Kong/2652/2006-like (clade 2C). Although Solomon Island/3/2006 (clade 2A) was in circulation in the 2006/2007 season, by the time the vaccine was created and distributed, clade A was replaced by clade B and clade C.

                  The differences between the clades can be seen in slide 9 from a CDC phylogram of NA. Clade 2 was distinguished from New Caldeonia by V223M and D385N. However, each sub-clade had a large number of addition non-synonymous changes. Clade 2A had M23I, H68N, G81E, K172R, S265T, D452G, while clade 2B had H49N, K82E, G248K, T286I, K329E, G357D, while clade 2C had S85P, R130K, M187I, I266M, L230I, V397I, T4531. Thus the NA sequences placed these isolates into three easily distinguished subclades.

                  The differences can also be seen in slide 8 which has an HA phylogram. However, there are a larger number of polymorphisms that distinguish all three sub-clades from New Caledonia (T90K, Y101H, K144E, R149K, R212K, T269N). Consequently, although each clade 2 sub-clade had specific distinguishing changes which were similar to the list above (K81R and V132T for clade A, D45N, K149R, R192K, E276K for clade B, and S46N, R192M, A193T, T197K for clade C.

                  Thus, even though the three sub-clades are easily distinguished by phylogenetic analysis, the 6 HA polymorphism that distinguish clade 2 from clade 1 led to the classification of the clade 2B and clade 2C circulating in the US as clade 2A, even though there were no clade 2A isolates in circulation in the US, or anywhere else in the 2007/2008 season (as indicated by the various 2007/2008 phylograms, including another from the CDC, which were recently released as well as additional 2007/2008 isolates from Europe, Asia, Africa, and South America. In all cases only clade 2B and 2C were circulation in the 2007/2008 season.

                  Thus, the H1N1 vaccine that targeted Solomon Island/3/2006 (clade 2A) which was circulating with clade 2B and 2C in 2006/2007 had reduced efficacy in 2007/2008 because clade 2A had been completely replaced by clade 2B and clade 2C.

                  Attempts to remedy this mis-match led to the changing of the H1N1 target for the 2008/2009 season from Solomon Island/3/2006 (clade 2A) to Brisbane/59/2007 (clade B).

                  However, while the mis-matched H1N1 was used to vaccinate worldwide in 2007/2008, clade 2B was spreading resistance to both neuraminidase inhibitors, Tamiflu (oseltamivir) and Relenza (zanamivir), while clade 2C was spreading resistance to the M2 channel blockers, amantadine and rimantadine.

                  The resistance to Tamiflu has captured the most attention. In Norway, the majority of H1N1 isolates have H274Y. Percentages above 50% have been reported in Norway and double digit frequencies have been reported in many northern countries, including France, Russia, and Canada. The H274Y has appeared on multiple Brisbane clade 2A sub-clades, supporting independent introductions via recombination. This pattern has also been see in Relenza resistance which was on clade 2A in 2006/2007 and in clade 2B in 2007/2008. The vaccine mismatch has allowed clade 2B to spread worldwide, facilitating the spread of Tamiflu resistance.

                  The mismatch for H1N1 was in addition to mismatches with H3N2 and influenza B, which has led to a 2008/2009 vaccine that has replaced all three viral targets.




                  Comment


                  • #10
                    Re: Evolution of Tamiflu Resistance H274Y

                    <big><big>Commentary
                    </big></big>
                    H1N1 Tamiflu Resistance at 100&#37; in South Africa
                    Recombinomics Commentary 23:50
                    July 18, 2008

                    In South Africa, a total of 90 A(H1N1) viruses have been isolated during the 2008 influenza season to date, and all of the 23 influenza A(H1N1) viruses tested by the WHO collaborating Centres in London and Melbourne were found to have resistance to oseltamivir by neuraminidase enzyme-inhibition assay.

                    None of these patients were receiving oseltamivir at the time of sampling, and no unusual clinical feature or underlying conditions have been found.

                    To date, preliminary test results show that the viruses carry the specific neuraminidase mutation (H274Y) that confers oseltamivir resistance in N1

                    From Chile, three of the 24 A(H1N1) viruses tested showed the specific neuraminidase mutation (H274Y).

                    The above comments from the WHO update on oseltamivir (Tamiflu) resistance indicate the frequency has now reached 100% in South Africa (based on the first 23 H1N1 samples tested). In the southern hemisphere, the 2008 flu season is ongoing. Consequently, Chile is also reporting H274Y in the current season. These isolates are almost certainly Brisbane/59 (clade 2B), which has been linked to the vast majority of Tamiflu resistant isolates from the 2007/2008 season.

                    Earlier positives from last season were on New Caledonia (clade 1) genetic backgrounds in the United States and Hong Kong (clade 2C) backgrounds in China. This season there have been multiple introductions of H274Y onto the Brisbane (clade 2B).

                    The expansion of H274Y has been facilitated by the vaccine mismatch, which targeted Solomon Islands (clade 2A) this season. There is no evidence for any clade 2A in circulation this season.

                    The expansion of H274Y via the Brisbane strain is cause for concern. It has now reached 100% in South Africa, which represents a growing reservoir of H274Y, which can clearly jump from one H1N1 clade to another, which is most easily explained by homologous recombination.

                    This polymorphism is identical to the H274Y on H5N1, suggesting that oseltamivir will have limited value for blunting an H5N1 pandmeic.




                    Comment


                    • #11
                      Re: Evolution of Tamiflu Resistance H274Y

                      Originally posted by Sally View Post
                      <BIG><BIG>Commentary
                      </BIG></BIG>
                      Emergence of H1N1 Relenza Resistance In Pennsylvania Recombinomics Commentary 14:48
                      July 17, 2008

                      The recent explosion of H1N1 Tamiflu (oseltamivir) resistance worldwide has focused attention on the other neuraminidase inhibitor, Relenza (zanamivir). Recently deposited H1N1 sequences from Asia had a novel polymorphism, Q137K, which confer resistance to Relenza (see list below).

                      A recently released NA sequences from Pennsylvania, A/Pennsylvania/01/2008, contains a mixture which encodes for both Q136 and Q136K. Like the more recent isolates from Asia, this isolate is on a clade 2B (Brisbane) background. In contrast, the earlier isolates were on a clade 2A (Solomon Islands) background.

                      Moreover, the introductions onto each background were independent suggesting that the Q136K polymorphism is spreading among H1N1 backgrounds by the same mechanism that is spreading the Tamiflu resistance H274Y onto multiple genetic backgrounds.

                      Like the spread of G743A on clade 2.2 backgrounds, this sudden and concurrent spread of the same polymorphism onto multiple genetic backgrounds is most easily explained by homologous recombination.

                      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






                      http://www.flutrackers.com/forum/showthread.php?t=74429
                      Q137K should be Q136K
                      Last edited by AlaskaDenise; July 27, 2008, 05:43 AM. Reason: requested correction made above and in original thread

                      Comment


                      • #12
                        Re: Evolution of Tamiflu Resistance H274Y

                        Emergence of H1N1 Relenza Resistance In New Jersey? Recombinomics Commentary 20:32
                        July 22, 2008

                        The recent explosion of oseltamivir (Tamiflu) resistance in H1N1 has focused attention on the emergence of resistance against all approved anti-virals. H5N1 clade 1 had two resistance markers for the amantadines, which included M2 S31N. Several years ago S31N began to appear in H3N2 seasonal flu and approached 100% in most countries, This was followed by appearance of S31N in H1N1, which has been limited to clade 2C (Hong Kong). The S31N level in clade C in the United States appears to be near 100%. Resistance to Amantadines has been seen previously, but not at these levels, indicating S31N did not reduce the fitness of H3N2 or H1N1.

                        However, the emergence of H274Y in NA was a surprise because a fitness penalty had been previously described. H274Y was also reported in H5N1 in patients treated with Tamiflu, as well as wild birds. The presence of H274Y in wild birds indicated there was not a fitness penalty in H5N1, but the recent data on seasonal H1N1 indicated there was no penalty in H1N1 either.

                        H274Y began to appear in the 2006/2007 season in patients who had not been treated with Tamiflu. Isolates from the United States had H274Y on a New Caledonia background (clade 1), while isolates in China had H274Y on a Hong Kong (clade 2C) background. The presence of H274Y on two distinct genetic backgrounds suggested movement by homologous recombination.

                        However, this season H274Y levels exploded worldwide. Initial reports cam from Norway, where more than50% of H1N1 isolates had H274Y. High levels were also seen in Russia, France, and Canada, but many countries had levels above 10%. Most recently the level rose to 100% in the first 23 samples tested in South Africa. The explosion of H274Y was in Brisbane (clade 2B), although phylogenetic analysis identified multiple introductions into clade 2B, providing additional evidence for recombination.

                        In addition to oseltamivir resistance, additional H1N1 resistance was found in Asia. This resistance (Q136K) was for zanamivir (Relenza) and was on a Solomon Island (clade 2A) background during the 2006/2007 season. It then jumped to a clade 2B background in the 2007/2008 season.

                        This season it also appeared as a mixture in a sample from Pennsylvania. That sequence had a mixed signal of the first position of the 137 codon, signaling a mixture of wild type and Q136K. More recently an isolate from New Jersey, A/New Jersey/08/2008, was identified which also had a mixed signal in the 137 codon. However, in this patient the mixture was at the second position, signaling wild type and Q136R. It is likely that this change will also generate Relenza resistance because both changes reflect a switch from an acidic to a basic amino acid. The amino acid sequences from both isolates were identical except for position 137 raising concnerns that the deposited sequences may represent quasi-species. Plaque purification and sequencing of the clones would be useful.

                        The appearance of Relenza resistance follows Tamiflu resistance and Amantadine resistance in H1N1, which creates significant pandemic concerns, since the above drugs represent the entire anti-viral arsenal currently approved for seasonal or avian influenza.




                        Comment


                        • #13
                          Re: Evolution of Tamiflu Resistance H274Y

                          <big><big>Commentary
                          </big></big>
                          H1N1 Clade 2C Amantadine Resistance at 100% in United States?
                          Recombinomics Commentary 14:22
                          July 21, 2008

                          Adamantane resistance continues to be high among influenza A (H3N2) viruses with 524 (99.8%) of 525 influenza A (H3N2) viruses tested being resistant to the adamantanes. Adamantane resistance among influenza A (H1N1) viruses has been detected at a lower level. Of the 918 influenza A (H1N1) viruses tested, 98 (10.7%) were resistant to the adamantanes. None of the oseltamivir-resistant influenza A (H1N1) viruses identified during the 2007--08 season were resistant to adamantanes.

                          The above comments from the recent CDC MMWR report on influenza in the United States is confusing on the breakdown of H1N1 isolates in the past season. Although many of the earlier isolates were classified as Solomon Island/3 (clade 2A), phylogenetic analysis fails to identify any clade 2A isolates. Instead the isolates in the United States were either Brisbane/59 (clade 2B) or Hong Kong/2652 (clade 2C). Clade 2C isolates collected by the CDC was largely confined to western states, although isolates collected by the US Air Force in Georgia (age distribution suggests these isolates were from military personnel) were also clade 2C.

                          The frequency of CDC isolates approximates the 10% reported above for amantadine resistance (M2 S31N) in H1N1, suggesting that all clade 2C isolates are Amantadine resistance. This interpretation is support by the fact that all oseltamivir resistant (NA H274Y) samples in the United States in the past season were clade 2B.

                          Thus, the pattern of oseltamivir is breaking down along sub-clade lines. All H1N1 amantatine resistance in the US is clade 2C, and appears to be in virtually all Clade 2C isolates. Oseltamivir resistance is at a lower level (10-20%), but all H1N1 isolates with H274Y are Clade 2B. However, this number may increase because oseltamivir levels in South Africa have reached 100% (on first 23 samples tested), and none have amantadine resistance, suggesting all are clade 2B.

                          The above data raises concerns that H1N1 seasonal flu is evolving toward anti-viral resistance in all isolates, with clade 2B carrying resistance to oseltamivir, and clade 2C carrying resistance to the amantadines.

                          These dramatic increases in resistant reservoirs raises serious concerns about the utility of these anti-virals to control or blunt an H5N1 pandemic, were both H274Y and S31N have been reported previously.




                          Comment


                          • #14
                            Re: Evolution of Tamiflu Resistance H274Y

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                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/46/2008(H1N1)) hemagglutinin (HA) gene, partial cds
                            gi|195661112|gb|EU914916.1|[195661112]
                            </TD></TR></TBODY></TABLE><!--docsumok 195661110 195661110 1 0 976-->
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                            gi|195661110|gb|EU914915.1|[195661110]
                            </TD></TR></TBODY></TABLE></DT></DL>
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                            gi|195661108|gb|EU914914.1|[195661108]
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                            gi|195661106|gb|EU914913.1|[195661106]
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                            gi|195661104|gb|EU914912.1|[195661104]
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                            gi|195661102|gb|EU914911.1|[195661102]
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                            gi|195661100|gb|EU914910.1|[195661100]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661098 195661098 1 0 976--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661098 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="8">8: EU914909</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661098 = [ ["TitleText","Reports"]];var Reports195661098 = [ ["UseLocalConfig","Reports195661098","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661098&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914909'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914909'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/10/2008(H1N1)) hemagglutinin (HA) gene, partial cds
                            gi|195661098|gb|EU914909.1|[195661098]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661096 195661096 1 0 1413--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661096 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="9">9: EU914908</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661096 = [ ["TitleText","Reports"]];var Reports195661096 = [ ["UseLocalConfig","Reports195661096","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661096&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914908'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914908'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/45/2008(H1N1)) neuraminidase (NA) gene, complete cds
                            gi|195661096|gb|EU914908.1|[195661096]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661094 195661094 1 0 1413--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661094 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="10">10: EU914907</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661094 = [ ["TitleText","Reports"]];var Reports195661094 = [ ["UseLocalConfig","Reports195661094","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661094&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914907'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914907'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/36/2008(H1N1)) neuraminidase (NA) gene, complete cds
                            gi|195661094|gb|EU914907.1|[195661094]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661092 195661092 1 0 1413--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661092 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="11">11: EU914906</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661092 = [ ["TitleText","Reports"]];var Reports195661092 = [ ["UseLocalConfig","Reports195661092","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661092&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914906'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914906'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/35/2008(H1N1)) neuraminidase (NA) gene, complete cds
                            gi|195661092|gb|EU914906.1|[195661092]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661090 195661090 1 0 1413--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661090 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="12">12: EU914905</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661090 = [ ["TitleText","Reports"]];var Reports195661090 = [ ["UseLocalConfig","Reports195661090","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661090&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914905'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914905'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/33/2008(H1N1)) neuraminidase (NA) gene, complete cds
                            gi|195661090|gb|EU914905.1|[195661090]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661088 195661088 1 0 1413--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661088 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="13">13: EU914904</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661088 = [ ["TitleText","Reports"]];var Reports195661088 = [ ["UseLocalConfig","Reports195661088","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661088&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914904'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914904'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/14/2008(H1N1)) neuraminidase (NA) gene, complete cds
                            gi|195661088|gb|EU914904.1|[195661088]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661086 195661086 1 0 1413--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661086 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="14">14: EU914903</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661086 = [ ["TitleText","Reports"]];var Reports195661086 = [ ["UseLocalConfig","Reports195661086","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661086&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914903'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914903'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/21/2008(H1N1)) neuraminidase (NA) gene, complete cds
                            gi|195661086|gb|EU914903.1|[195661086]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661084 195661084 1 0 1401--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661084 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="15">15: EU914902</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661084 = [ ["TitleText","Reports"]];var Reports195661084 = [ ["UseLocalConfig","Reports195661084","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661084&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914902'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914902'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/CapeTown/26/2008(H1N1)) neuraminidase (NA) gene, partial cds
                            gi|195661084|gb|EU914902.1|[195661084]
                            </TD></TR></TBODY></TABLE></DT></DL>
                            <!--docsumok 195661082 195661082 1 0 1401--><DL><DT><TABLE cellPadding=0 width="100%"><TBODY><TR><TD style="WHITE-SPACE: nowrap" vAlign=top width="20%"><INPUT id=UidCheckBox type=checkbox value=195661082 name=EntrezSystem2.PEntrez.Nuccore.Sequence_Result sPanel.Sequence_RVDocSum.uid sid="16">16: EU914901</TD><TD vAlign=top align=left>
                            Reports<SCRIPT language=JavaScript1.2><!--var PopUpMenu2_LocalConfig_Reports195661082 = [ ["TitleText","Reports"]];var Reports195661082 = [ ["UseLocalConfig","Reports195661082","",""], ["ASN.1","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=as n'","",""], ["XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=xm l'","",""], ["Summary","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=do csum'","",""], ["Brief","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=br ief'","",""], ["FASTA","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=fa sta'","",""], ["TinySeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=fa sta_xml'","",""], ["GenBank","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=gb '","",""], ["INSDSeq XML","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=gb c_xml'","",""], ["GenBank(Full)","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=gb withparts'","",""], ["GI List","window.top.location='/entrez/viewer.fcgi?list_uids=195661082&db=nuccore&dopt=gi '","",""], ["Graphic","window.top.location='?cmd=Show&doptcmdl =graph&db=nuccore&term=EU914901'","",""], ["Revision History","window.top.location='/entrez/sutils/girevhist.cgi?val=EU914901'","",""]]--></SCRIPT> </TD><TD vAlign=top align=right>
                            </TD></TR><TR><TD style="PADDING-LEFT: 2.8em" vAlign=top align=left colSpan=3>Influenza A virus (A/Johannesburg/12/2008(H1N1)) neuraminidase (NA) gene, partial cds
                            gi|195661082|gb|EU914901.1|[195661082] </TD></TR></TBODY></TABLE></DT></DL>

                            Comment


                            • #15
                              Re: Evolution of Tamiflu Resistance H274Y

                              New sequences with H274Y


                              gb|EU914908.1| Influenza A virus (A/Johannesburg/45/2008(H1N1... 26.3 610
                              gb|EU914907.1| Influenza A virus (A/Johannesburg/36/2008(H1N1... 26.3 610
                              gb|EU914906.1| Influenza A virus (A/Johannesburg/35/2008(H1N1... 26.3 610
                              gb|EU914905.1| Influenza A virus (A/Johannesburg/33/2008(H1N1... 26.3 610
                              gb|EU914904.1| Influenza A virus (A/Johannesburg/14/2008(H1N1... 26.3 610
                              gb|EU914903.1| Influenza A virus (A/Johannesburg/21/2008(H1N1... 26.3 610
                              gb|EU914902.1| Influenza A virus (A/CapeTown/26/2008(H1N1)) n... 26.3 610
                              gb|EU914901.1| Influenza A virus (A/Johannesburg/12/2008(H1N1... 26.3 610

                              Comment

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