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H5N1 Sequence Analysis of North Sumatra Cluster

Recombinomics Commentary

May 25, 2006

The CDC head said the genetic sequencing of viruses from the cluster so far has yielded four main findings:

The isolates are all "virtually identical," implying a single source.

They are susceptible to the antiviral drug Tamiflu (oseltamivir).

"There is no evidence of motif changes in the particular areas of the genes that are responsible for how the virus binds to the respiratory tract of people."

The isolates are very similar to viruses previously collected from poultry in the region.

The above comments from the CDC are similar to comments from Hong Kong.  Both groups receive human samples from Indonesia as indicated in the WHO update.  However, as with the earlier WHO updates, more information is available from what is not said in the reports.  Since only part of human sequence has been made public (HA and NA from the first confirmed case in July of 2005), more sequence interpretations come from short and well parsed comments, such as those above.

The first two confirmed cases in Indonesia were associated with short descriptions which contained subtle differences.  The released sequence from the first case in 2005 has a novel cleavage site (RESRRKKR), which is why it was not called “virtually identical” but was said to have ”high homology” with poultry sequences, which have the more common cleavage site (RERRRKKR).  The second sequence in 2005 was called “essentially the same” as poultry (as opposed to essentially the same as the first human sequence), indicating it had the RERRRKKR cleavage site.  Thus, there were two sequences in human cases in the Jakarta area. 

A subsequent report indicated all human sequences from the area had RESRRKKR which did not match any known poultry source, which created a problem since all WHO updates indicated the human cases were linked to H5N1 in poultry.  The only animal in the Jakarta area with a sequence with RESRRKKR was not a bird, but a cat, raising serious questions about origins and transmission, since many of the patients in the area were from familial clusters with 5-10 day gaps, indicating human-to-human transmission (H2H).  These clusters included both of the above sequences, indicating both cleavage sites were linked to H2H, but only one was linked to poultry.

The comments above indicating that the sequences from the Sumatra cluster were “virtually identical” to each other and “very similar” to poultry isolated previously from the area indicates a poultry source infected the index case, but the subsequent infections were from the index case or other family members and the normal incubation time of 2-5 days suggests that there were multiple transmissions within the family that were not linked to the index case.

The cleavage site would be the common poultry sequence of RERRRKKR, but the failure to mention amantadine sensitivity suggests the cluster sequences were amantadine resistant, as has been seen previously in poultry isolates from Indonesia.

Thus, the only antiviral mentioned was Tamiflu susceptibility, and the United States is shipping Tamiflu to “Asia”.  However. local media reports indicate that the patients in the cluster were treated with 3 X 75 mg Tamiflu, and all but one died, even though the later cases seem to have been hospitalized shortly after developing symptoms.  The exact times are not clear because the onset dates for all relatives other than the last fatality, who refused Tamiflu treatment, were not included in the WHO update.

The “resistance” to the Tamiflu treatment may have been due to another change, which is not related to the receptor binding domain, which the above comments indicate the human isolates match an avian motif.  That change, which has been seen in H5N1 human cases in Asia as well as dog and wild and domestic cat sequences in Thailand, is PB2 E627K, which may be why the cluster sequences are “virtually identical” to each other, but “very similar” to the poultry sequences, which have not been reported to have PB2 E627K.  The only bird H5N1 sequences with E627K are the Qinghai strain, which is quite distinct from Indonesian bird or human HA and NA sequences (no other human genes have been released from Indonesia)..

The accuracy of the above analysis can be easily determined by simply releasing the full Indonesian sequences, which have been sequestered at the private WHO database at Los Alamos since August of 2005.

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