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Human H5N1 Sequences from North Sumatra Indonesia

Recombinomics Commentary

May 23, 2006

Full genetic sequencing of two viruses isolated from cases in this cluster has been completed by WHO H5 reference laboratories in Hong Kong and the USA. Sequencing of all eight gene segments found no evidence of genetic reassortment with human or pig influenza viruses and no evidence of significant mutations. The viruses showed no mutations associated with resistance to the neuraminidase inhibitors, including oseltamivir (Tamiflu).

The human viruses from this cluster are genetically similar to viruses isolated from poultry in North Sumatra during a previous outbreak.

Although the above WHO description has more detail than earlier description of the first confirmed human case in Indonesia

Genotyping of the PCR-amplified isolate from the confirmed case shows high homogeneity with other H5N1 isolates from poultry in Java, and no evidence of reassortment.

Or the second confirmed case

The sequence showed that the virus was essentially the same A(H5N1) avian influenza virus that had already been circulating in poultry in Indonesia, he said.

The sequence from the first case has been made public and it had a number of features that distinguishing it from poultry in Java.  There was high homology with the poultry isolates, but the sequence had a novel HA cleavage site as well as an extra glycosylation site on HA.  Subsequent reports indicated almost all isolates from West Java / Lampung had the novel cleavage site raising question of the origin of the H5N1 infecting people in the area.

In contrast, as noted above, the second sequence was "essentially the same" as avian influenza. But not considered essentially the same as the first isolate, suggest the second isolate from Indonesia was the sequence without the novel cleavage site. 

For the index isolate, only the HA and NA sequence of the CDC has been released.  It is likely that the described Hong Kong version of the sequences are virtually identical.

The two North Sumatra sequences sound like they are closely related to each, which would have been expected  for isolates from relatives infected around the same time in the same location. The comments on reassortment are not surprising.  H5N1 has never been shown to reassort with human or swine sequences although H5N1 isolates have acquire mammalian polymorphism via recombination.  Similarly, the H1N1 pandemic strain of 1918 had no evidence of reassortment, but had polymorphisms from human and swine H1N1 isolates from the early 1930's indicating the pandemic strain was also a recombinant between two H1N1 serotypes.  Swine H5N1 is closely related to avian H5N1 and neither are efficiently transmitted to humans.

However, the North Sumatra cluster was generated by extended human to human transmission (H2H), covering at least three generations (H2H2H2H), raising questions about acquired plymorphisms which may not be considered "significant" by the sequencers.  Interestingly they only spoke of wild type NA sequences, resulting in Tamiflu sensitivity.  This would be expected, since yesterday the United States announced deployment of its Tamflu reserves to Asia.

However, yesterday WHO announced use of amantadines in combination with Tamiflu, but the above description fails to indicate that the isolates are amantadine sensitive.  Since prior poultry isolates in Indonesia have been shown to be amantadine resistant, but none have been shown to be Tamiflu resistant, the exclusion of comments on amantadine suggests the human isolates, like some of the poultry isolates, are amantadine resistant.

Similarly, there is no mention of the presence of the PB2 polymorphism, E627K, which when combined with a wild type H5N1 cleavage site is almost always fatal in mammals.  This change has been found in human H5N1 isolates from the 1997 outbreak in Hong Kong as well as outbreaks in more recent outbreaks in Vietnam and Thailand.  The change has also been found in fatal infections of wild and domestic cats and well as a domestic dog.

However, such interpretations of carefully parsed updates should not be necessary.  All eight gene segments of all of the H5N1 in Indonesia should be released.  The sequences in West Java raise serious question about the origin of the infections and the determine of the what is and is not significant in the current isolates should be determined by the scientific community and not a small group of sequencers overly focused on reassortment, which was also not demonstrated in earlier lab experiments mixing 1997 avian H5N1 with human H3N2 genes and will probably not be demonstrated when 2004 H5N1 is mixed with human H3N2 genes.

The current cluster has extended H2H transmission chains.  Careful analysis of the full sequences could provide genetic clues on possible reason why the transmission was efficient and deadly.  Seven of the eight cluster members have died, making this cluster the deadliest reported to date.  This deadly combination may be due to a wild type cleavage site of RERRRKKR coupled with a PB2 E627K polymorphism, which in the past has been fatal in almost all human infections coupled with the RERRRKKR cleavage site.

However, there is no reason to be speculating on the sequestered sequences. 

They should be released immediately.

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