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Progress on Release of Indonesian H5N1 Sequences

Recombinomics Commentary

June 1, 2006

``We have not received any request to share it with GenBank,'' Kandun said yesterday in an interview from Jakarta. ``If there was a request, and it's clear that it is in the public interest to do so, why not? I would surely recommend it to the health minister.''

``We think it's important to share this information so that everyone can have a better understanding of what's going on,'' said Maria Cheng, a spokeswoman for the World Health Organization in Geneva.

The above comments from the director-general of disease control in Indonesia as well as a spokesperson for the WHO would appear to pave the way for the release of H5N1 bird flu sequences sequestered at the WHO private database.  Release of these sequences is important for determining how H5N1 is evolving in Indonesia.

The recent cluster in north Sumatra was the largest and most deadly in Indonesia and had clear examples of multiple human-to-human transmissions.  The description of the sequences provided information of the lack of reassortment and "significant mutations".  These significant mutations appear to be limited to HA positions 226 and 228 in the receptor binding domain.  However, usually resistance markers for the two classes of anti-virals are determined as well as position 627 in the PB2 gene.

The WHO report indicated the H5N1 was sensitive to neuraminidase inhibitors, but failed to mention sensitivity to ion channel blocks, the amantadanes.  This omission suggested the isolates were amantadane resistant with M2 S31N.  The high concentrations of H5N1 in the nose ands throat also raised the possibility of acquisition of PB2 E627K.  Moreover, the similarity to bird isolates suggest the HA cleavage site was the wild type sequence, RERRRKKR.

The amantadine resistance would affect treatment choices and the acquisition of PB2 E627K may make the H5N1 more transmissible, which would account for the size of the cluster and length of the transmission chain.

In addition to questions concerning the sequences in Sumatra, there are additional concerns about the sequence from West Java, which have a novel cleavage site, RESRRKKR, which has not been reported in bird sequences anywhere. This difference between in the human and bird sequences raises questions on the origin of infections.  Since most H5N1 testing is limited to suspect cases that have had recent exposure to dead and dying birds, cases due to infection by H5N1 from an alternate reservoir may be overlooked.

Publishing of the sequences allows for sophisticated analysis that can determine the source of the infections.  WHO consultants believe H5N1 evolves via reassortment and random mutation.  However, compelling evidence indicates change via recombination is much more common.  Since acquisitions of polymorphisms are derived from other viruses via dual infection, the acquired polymorphisms can be used to identify donor sequences and viruses.  Thus, polymorphisms can be used to trace origins, and this tracing is most efficient when a robust database is available.

Therefore release of the sequences allows important questions of origins of infections to be determined.  These sequestered sequences as well as additional sequences from animal reservoirs will aid in the identification and elimination or control of reservoirs causing the increasing number of H5N1 infections in humans and other hosts.

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