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Novel Human H5N1in Indonesia Raises Pandemic Concerns

Recombinomics Commentary

May 17, 2006

The recent large cluster in Indonesia has refocused attention on human-to-human transmission and the novel cleavage site in human HA H5N1.  Although cleavage sites can change, there has been no evidence for a species specific change. 

The first H5N1 isolated in Asia in 1996 in the Guangdong goose had the highly pathogenic sequences of RERRRKKR.  That sequence has found in the human cases in 1997 as well as most human and animal isolates in Asia.  In 2005 milder cases in northern Vietnam had been noted and those cases had lost an R in the cleavage site, which was then RERRKKR.  Recently, China released human sequence data and those sequences were closely related to a Fujian strain, which was missing a K, giving the sequence RERRRKR.  However, that cleavage site had been found in a duck in Fujian province and had been in bird H5N1 sequences dating back to 2003.  The Qinghai strain of H5N1 has a unique sequence of GERRRKKR, which is found in virtually all of the Qinghai isolates, including human isolates from Iraq and Egypt.

Thus, although the cleavage can change, the change is typically found in both mammals and birds.  The bird H5N1 sequences from Indonesia have the common sequence of RERRRKKR and the recent sequences from Indonesia span isolates from 2003 to 2005.  However, the human isolate from 2005 has the novel sequence RESRRKKR.  This sequence is not found in any of the avian H5N1 Indonesian sequences or any other H5N1 sequence at GenBank.  However, the one sequence is not definitive because there are some novel sequences that have not become widespread and may lack significance.

However, a report that a cat sequence from Indonesia has the same change is cause for concern, as is the comment that many additional human sequences from Indonesia also have the same change.  A large number of human isolates with RESRRKKR, in the absence of any avian sequences with RESRRKKR, would indicate that birds were not a source of the human H5N1 infections.

These data raise concerns that the human sequences are due to infection by H5N1 from other humans or other mammals.  Since there have been over 30 confirmed cases of human H5N1 in Indonesia, the WHO private database would have the answer to the frequency of human H5N1 with the novel cleavage site. 

If that data validates the comment that several human and cats sequences have the novel site, then the claims that the human cases were due to poultry infections would be suspect and the limited testing, which requires association with dying poultry should be expanded to those who have bird flu symptoms, but lack a poultry connection.
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