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Accelerating H5N1 Genetic Change Increases Pandemic Risk
Recombinomics Commentary
September 17, 2006

The recent matching of the dominant genotypes of human H5N1 in Indonesia highlights the increasing genetic diversity in Indonesia. This growing complexity increases pandemic risk because co-circulating genomes lead to more productive recombinations, which lead to accelerated genetic change.

A recent analysis of H5N1 in Indonesia (see linked phylogram) demonstrated a relationship between geographical location and genetic relatedness.  The avian isolates formed three groups.  Group A and B were in eastern Indonesia, while group C was in western Indonesia.  These bird groupings were also loosely associated with human cases.  The vast majority of reported human cases were on the island of Java.  They were concentrated in western Java in Jakarta and adjacent regions.  Although the human isolates were distinct, they were most closely related to the A group from eastern Indonesia.  Similarly, the Karo cluster from North Sumatra was most closely related to the C group, which was largely composed from isolates from Sumatra, including those near Karo.

However, there were no true matched between the human and avian isolates.  All human isolates, other than the Karo cluster and one patient from the Jakarta area, had a novel cleavage site, which was not found in any bird isolates.  Similarly, there were additional changes associated with the novel cleavage site, and these additional changes were also not found in bird isolate.  A few weeks ago the first bird isolate with the novel cleavage site was announced.  However, this isolate was a close match to a small subset of human cases from 2005 and one case from 2006.  The duck isolate was from Indramayu, but did not closely match human isolates from patients in Indramayu.

Last week two of the latest deposits did match the human sequences on Java.  However, the matches were in H5N1 from two chickens on Sumatra isolated in 2005.  Similarly, a match for the Karo cluster was found, but it was not in Karo or Sumatra.  Instead the match was in a duck isolate from East Java.  Thus, the close matches of the human sequences were not with bird isolates in the area of the human cases.

The increased number of sequences provided compelling evidence for a hidden reservoir.  Although WHO updates frequently cite contact with dead or dying poultry, there have been no matches between an isolate from a patient and an isolate from the dead or dying poultry in the area.  In Indonesia there have now been approximately 80 bird isolates sequenced and close to 100 human isolates from almost 50 patients, which have been collected for over a year, yet there is not a single match.

The match failure, coupled with the linkage to bird isolates from distant locations suggests that the human isolates come from an unknown genetic reservoir.  However, the evolving bird H5N1 genomes do impact the human isolates as evidenced by the rare matches with isolates from distant location.  Moreover, the loss of linkage between geography and genetic relatedness indicates the amount of co-circulation of related but distinct genomes is increasing.  Many of the recent isolates from eastern Indonesian are now most closely related to the C group from western Indonesia.  Similarly, there are additional examples of the A group from eastern Indonesia being isolated in western Indonesia.

Co-circulation is cause fro concern.  The 1918 pandemic strain arose via recombination between H1N1 from humans and H1N1 from swine.  In Hong Kong in 2001 there were two distinct strains of H5N1 co-circulating which lead to the formation of the Z genotype which is the dominant H5N1 genotype causing human fatalities.

H5N1 has subsequently formed a number of sub-clades which were recently selected as pandemic vaccine targets.  However, these sub-clades are being further sub-divided.  The group A, which is most like the human H5n1 on Java, is distinct from group C which is most like the human H5N1 in the Karo cluster.  These two groups have limited cross reactivity, and will likely become more diverse because of the co-circulation of the Indonesian strains, coupled with new sequences flying into the region via migratory birds.

As the level of co-circulation increases, the rate of genetic change in H5N1 will accelerate. 

This rapid genetic evolution is cause for concern.

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