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H5N1 H3N2 Reassortants Are Not Evolutionarily Fit

Recombinomics Commentary

July 31, 2006

an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.

The above comments from "Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model", published ahead of the press in today's Proceedings of the National Academy of Sciences adds more detail to earlier observations that H5N1 does not reassort well with human genes.  Most of the data in the above publication use an islate from 1997 for the transmission experiments, but additional test using H5N1 from 2003 and 2005 also indicated that the human gene decreased the ability of the reassortant to replicate efficiently.

These data had been discussed in 2004 and are not a surprise.  However, it is reassortment that is the used in WHO reports as well as government reports offering reassurance that H5N1 has not acquired complete human genes.  These reassurances offer little reassurance because H5N1 does not evolve via reassortment with human genes.

H5N1 has been evolving via recombination.  The changes are small but frequent.  Currently, there are at least four different versions of H5N1 bird flu circulating.  Clade 1 has caused reported human fatalities in Vietnam, Thailand, and Cambodia.  For clade 2, there are at least three distinct versions.  One is in Indonesia.  Most of the human cases in Indonesia have a novel HA cleavage site that has not been reported in any avian isolate.  In the current paper discussed above, the Indonesia/5/05 isolate was detected in respiratory secretions of infected ferrets.  A second clade 2 version is the Fujian strain, which is represented in all public human isolates from China in 2005 and 2006.  Thus strain has also been detected in birds in Laos and Malaysia.  The third clade 2 strain is the Qinghai strain, that is being transported and transmitted worldwide by migratory birds.  There are multiple versions of this strain, but it has cause human fatalities in Turkey, Azerbaijan, and Egypt and has also caused a human infection in Djibouti.

H5N1 infections in long range migratory bird has lead to the spread of the strain into India, Afghanistan, Europe, the Middle East, and Africa.  Further spread is expected throughout the Americas, as H5N1 continues to evolve via recombination.  The Qinghai isolates have discordant polymorphisms, indicating this evolution is primarily, if not exclusively being driven by recombination.

H5N1 has acquired mammalian polymorphisms via recombination.  These acquisitions continue to drive H5N1 evolution.  The reassortment with human genes has not been demonstrated, and the current publication suggests that evolutionary pressures are stacked against H5N1 reassortment with human genes.

H5N1 can efficiently replicate in humans. It currently is not efficiently transmitted.  However, this transmission is primarily driven by H and reassortment and acquisition of human H1 or H3 would not create a pandemic strain, since it would have the current H1 or H3, for which most humans have immunity.  The current paper indicates that human internal genes in H5N1 ould decrease the replication capacity of the reassortant, which again indicates that creation of a pandemic H5N1 via reassortment is unlikely.

These data should focus attention on the changing, not swapping of genes.  The changing of genes is driven by recombination.

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