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  Date / Time: 7/15/2009 8:43 PM UTC

  1918 Pandenic H1N1 Human/Swine Recombination
  

  It has become almost common wisdom that the virus that caused the 1918 flu pandemic was an avian strain introduced into the human population shortly before the pandemic erupted. But a new study disputes that hypothesis, arguing instead that genes of the 1918 virus had circulated in mammalian hosts, most likely pigs and humans, for several years before 1918.
  
  The origins of the 1918 virus, which is estimated to have killed at least 20 million people, are still controversial. After painstakingly piecing together the genome of the extinct strain, a team led by virologist Jeffery Taubenberger, then at the Armed Forces Institute of Pathology in Washington, D.C., concluded in 2005 that the virus most closely resembled viruses of avian origin; the team suggested it had become transmissible between humans after a couple of key changes
  
  The above comments on the recent PNAS paper as well as the Nature paper in 2005 provides some background on the data supporting a human / swine origin of 1918.  The sequence of a 1917 avian isolate clearly demonstrated that avian sequences in 1917 were similar to current avian sequences and easily distinguished from mammalian sequences, such as pandemic 1918 H1N1, seasonal H1N1 and swine H1N1.
  
  The Nature paper of 2005 identified 10 polymorphisms which were said to be pandemic -specific because they were in the 1918 pandemic sequence but not avian sequences.  However, these markers were simply mammalian markers and were not only in the H1N1 1918 pandemic sequence but also in seasonal H1N1 and swine H1N1.  Thus, the markers did not identify changes that created a pandemic strain, but instead provided additional data supporting a human / swine origin of 1918, as had been seen from phylogenetic analysis.
  
  The swine origin is also supported by the recent Nature paper showing that sera from patients alive in 1918 had antibodies that not only saw the 1918 pandemic H1N1 strain, but also the current 2009 pandemic strain which is a swine H1N1.  Thus, both the antibody data as well as phylogenetic analysis support a mammalian (human and swine) origin of 1918.
  
  However, detailed analysis of the 8 gene segments of the 1918 virus show that it is a recombinant with alternating blocks of swine and human polymorphisms.  In fact approximately 90% of the polymorphisms in each of the eight gene segments can be found in two parental sequences, WSN/33 representing human H1N1 and swine/Iowa/15/1931 representing swine H1N1.  Although there are some avian polymorphisms, the vast majority of polymorphisms is mammalian and can in fact be found in two isolates from the early 1930's.
  
  These data have important implications for the current pandemic strain, because it is a swine H1N1 which can efficiently transmit in humans. It has spread throughout the human population worldwide, and now is in position for further adaptation to human host via recombination with seasonal H1N1, which is well adapted to humans.
  
  There are several obvious candidates in seasonal H1N1 which could significantly impact swine H1N1.  One of the 10 markers identified in the 2005 Nature paper was PB2 E627K.  This polymorphism is in virtually all influenza A seasonal flu isolates.  It allows for most efficient replication at 33 C, which leads to upper respiratory infections and a preference for seasonal spread, when cold temperatures keep the human nose close to the optimal temperature for E627K.  In contrast, the avian version, E627, allows for most efficient replication at 41 C, the body temperature of birds.  Since the swine H1N PB2 is avian, it has E627, which may lead to less efficient transmission in the winter, but higher transmission in the summer, and associated replication the lower respiratory tract.  E627K was reported in one isolate in Shanghai but was only found in the sequences from the original sample as well as the first clone.  The second clone had reverted back to E627.
  
  Another potential acquisition from seasonal H1N1 is H274Y.  Although this isn't a mammalian specific polymorphisms, it is present on almost 100% of seasonal H1N1 and has a history of jumping from one genetic background to another.  It has been reported in three pandemic swine isolates, including a patient traveling from San Francisco to Hong Kong who had not received oseltamivir, raising concerns of a fit pandemic H1N1 with H274Y.  Moreover, this isolate and other related isolates without H274Y also have a receptor binding domain change D225E, which may be important in establishing dominance via genetic hitching. A change at the same position, D225N, was associated with the establishment of H3N2 seasonal flu with adamantane resistance, S31N.
  
  Thus, the movement of swine H1N1 into the human population creates the environment for rapid adaptation to human hosts and the acquisition of key polymorphisms from seasonal H1N1, which could cause significant problems in the upcoming months.
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