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Unique Human H5N1 Bird Flu Sequences in Indonesia

Recombinomics Commentary

August 7, 2006

The human H5N1 Indonesian sequences sequestered at the WHO private database at Los Alamos were released to the public on Friday.  Prior to this release, only two sequences, the HA and NA of A/Indonesia/5/05 were public.  Thus was the first human isolate in Indonesia and was placed in the WHO data base by the CDC on August 1, 2005 and released on March 25, 2006.  The release on Friday dramatically increased the number of public sequences to 504 (8 gene sequences from 63 human isolates).

Phylogenetic trees of HA sequences in the private database were discussed at the recent meeting in Jakarta.  Most of the human sequences had the novel HA cleavage site RESRRRKKR.  However, these sequences, primarily from the Jakarta / West Java area, also had several additional changes in HA and they formed a separate branch on the tree.  Moreover, there were no avian sequences on this branch.

This lack of matching avian sequences raised concerns about the origin of the human H5N1.  As indicated above, the first human sequence was isolated in July, 2005.  The public avian sequences were from a wide geographical range in Indonesia, but most were collected prior to the first human case.  None of these 2003-2005 isolates had the novel cleavage site.  More recent collections were sent to Australia for analysis and those avian sequences were not included in the released data.

Analysis of the newly released data indicates that the human isolates with the novel cleavage site have a large number of unique polymorphism not found in any public Indonesian avian sequence, although the unique polymorphisms are clearly on an Indonesian genetic background.  These unique polymorphisms are only all eight gene segments adding additional evidence suggesting the majority of the human cases are not linked to avian H5N1 in Indonesia.

The acquired polymorphisms are not random.  As noted earlier for the first human sequences, they can frequently be found in other polymorphism on other H5N1 genetic backgrounds.  This same type of acquisitions have been noted in Qinghai isolates found in the Middle East, Europe, and Africa.  Although the isolates have a Qinghai genetic background, they are punctuated with a variety of shared polymorphisms whose distribution is far from random.  These polymorphism are acquired via recombination.

These acquisitions also can be used to trace origins.  The human sequences in Indonesia have a number of mammalian polymorphisms that are frequently found in isolates from humans, swine, dogs, and horses.  In addition, a cat isolate, A/feline/Indonesia/CDC1/2006, matches the majority of the human isolates in all eight gene segments.  A couple of the M polymorphisms are lusted below with isolates that share the polymorphism.

The presence of these polymorphism in mammalian isolates and the absence in Indonesian avian isolates, raises serious concerns about the origin of the H5N1 infections in Indonesia.

  ISDN137455  A/Feline/Indonesia/CDC1/06       2006  H5N1   
   ISDN133318  A/Indonesia/283H/2006                2006  H5N1   
   ISDN133325  A/Indonesia/286H/2006                2006  H5N1   
   ISDN138749  A/Indonesia/292H/2006                2006  H5N1   
   ISDN136850  A/Indonesia/304H/2006                2006  H5N1   
   ISDN140927  A/Indonesia/542H/2006                2006  H5N1   
   ISDN137450  A/Indonesia/CDC326/06               2006  H5N1   
   ISDN137452  A/Indonesia/CDC326n/06             2006  H5N1   
   ISDN137451  A/Indonesia/CDC326t/06              2006  H5N1   
   ISDN137453  A/Indonesia/CDC329/2006           2006  H5N1   
   ISDN137454  A/Indonesia/CDC357/06                2006  H5N1   
   ISDN181368  A/Indonesia/CDC523/2006            2006  H5N1   
   ISDN183298  A/Indonesia/CDC523E/2006          2006  H5N1   
   ISDN183306  A/Indonesia/CDC523T/2006          2006  H5N1   
   ISDN183314  A/Indonesia/CDC582/2006             2006  H5N1   
   ISDN183702  A/Indonesia/CDC610/2006             2006  H5N1   
   ISDN183750  A/Indonesia/CDC634/2006             2006  H5N1   
   ISDN183758  A/Indonesia/CDC634P/2006          2006  H5N1   
   ISDN183766  A/Indonesia/CDC634T/2006           2006  H5N1   
   ISDN132407  A/Indonesia/239H/2005                    2005  H5N1   
   ISDN132415  A/Indonesia/245H/2005                    2005  H5N1   
   ISDN128028  A/Indonesia/6/2005                           2005  H5N1   
   ISDN137460  A/Indonesia/CDC287e/05                2005  H5N1   
   ISDN137449  A/Indonesia/CDC292t/05                  2005  H5N1   
   DQ124152     A/canine/Florida/43/2004                  2004  H3N8   
   DQ124197     A/canine/Texas/1/2004                      2004  H3N8   
   CY010565     A/swine/Spain/54008/2004                2004  H3N2   
   DQ124160     A/canine/Florida/242/2003                 2003  H3N8   
   DQ124162     A/equine/Massachussetts/213/2003 2003  H3N8   
   DQ124188     A/equine/Ohio/1/2003                         2003  H3N8   
   DQ222916     A/equine/Wisconsin/1/03                   2003  H3N8   
   AY855344      A/equine/Kentucky/5/02                     2002  H3N8   
   DQ376666     A/chicken/Taiwan/1205/01                 2001  H6N1   
   CY004940      A/mallard/Alberta/30/2001                 2001  H4N8   
   AF213916      A/Swine/Italy/25823/94                       1994  H3N2   
   AJ311508      A/swine/Cotes d'Armor/3633/84        1984  H3N2   
   M55478         A/Swine/Germany/2/81                        1981  H1N1   
   CY004984     A/mallard duck/Alberta/283/1977       1977  H8N4  

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