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Novel HA Cleavage Site In H5N1 Chickens on Sumatra
Recombinomics Commentary

September 14, 2006

Nineteen H5N1 sequences from birds in Indonesia were made public today at Los Alamos.  The HA bird flu sequences were collected in 2005 from multiple locations and were sequenced in Australia as part of an effort focused on the origins of the H5N1 infections in patients.  Although prior public sequences included 28 isolates from 2005 and 6 isolates from 2006, only one had the novel cleavage site.  Moreover, that isolate had a silent change in the cleavage site, which was present in a few human isolates from late 2005 and early 2006.  Thus, the finding of the cleavage site in poultry was difficult, even though it was detected in all but one human isolate in 2005 and all isolates in 2006 other than the Karo cluster.

Analysis of the 19 sequences that were made public today identified two chicken samples with the novel cleavage site (A/Chicken/Pakun Baru/BPPV-II/2005 and A/Chicken/Murao Jambi/BBPV-II/2005). Moreover, these two isolates did not have the silent change in the cleavage site, so they also matched the human isolates at this position, as well as a number of additional changes that had not previously been identified in poultry isolates.

However, the match in the two isolates raised additional questions about the source of the human infections.  Both isolates were from chickens on Sumatra, but the human isolates were from Java.  Most of the reported human infections have been in western Java, yet the only reported bird isolate on Java with the novel cleavage site has been the earlier duck isolate, which was a poor match for most human isolates.  Moreover, since the chicken isolates were in 2005 and on Sumatra, the issues of collection dates or sites does not explain the large number of isolates that do not match.  Of the 53 bird H5N1 sequences from isolates in 2005 and 2006, only three have the novel cleavage site.  However, all but one human isolate in 2005 has the novel cleavage site, and all 2006 human isolates except the Karo cluster has the cleavage site.  These data point toward a reservoir for human H5N1 other than domestic poultry.

Many of these isolates have wild bird sequences, including the human cases, and evidence continues to suggest that humans can have very mild infections of H5N1.  The latest case added retrospectively to H5n1 confirmed cases is from West Sumatra.  The patient had mild symptoms that did not included a fever, yet he has tested positive for a four fold or greater increase in neutralizing antibody levels after caring for his H5N1 positive sister.  Similarly, the third confirmed case in Indonesia was the nephew of the second confirmed case in Indonesia.  He also had a mild case of H5N1 and had influenza symptoms for a few days, although his aunt died.

These milder cases raise the possibility that H5N1 is maintained in populations that do not also have associated severe symptoms.  H5N1 has been isolated from asymptomatic swine in Indonesia and antibodies have been detected in asymptomatic wild birds.

Thus, the two chicken isolates in Sumatra in 2005 do not explain the almost universal finding of a novel cleavage site and associated changes in human H5N1 in Indonesia and further surveillance of alternate sources, including humans, would be useful.

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