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Molecular Epidemiology of 2005 H5N1 NA Gene

Recombinomics Commentary

July 3, 2005

Recently, 10 HA sequences from 2005 isolates in Vietnam were made public.  Although the Manila update by WHO focused on genetic changes in human isolates from northern Vietnam, including the ARG deletion in the HA cleavage site, the 10 sequences at the flu repository at Los Alamos National Labs show that all 10 sequences have the same 3 nucleotide deletion that had been found in earlier isolates, including an isolate from a chicken in Hau Giang in 2004.  This isolate was collected in the summer of 2004, which there was an outbreak of human cases in Hau Giang in the south and Ha Tay in the north.  2005 isolates from Ha Tay and several provinces in the north had the deletion, but so did the four isolates from the south (from Ha Tay and Tien Giang provinces).  Thus, it is clear that the ARG deletion was widespread in Vietnam in 2005, although there is only one 2004 example at Genbank or Los Alamos.

Analysis of the 10 NA sequences from 2005 identifies additional changes that are unique to the 2005 isolates.  These changes are not in the 2004 Hau Giang sequence, suggesting additional sequences were imported into the area.  These changes are not well represented in the existing database of H5N1 sequences.  However, some are found in N1 sequences from wild birds with H9N1, H6N1, and H1N1 sero-types, while others are from H3 serotypes such as H5N3, H16N3 or other migratory bird sero-types like H11N6.  These sero-types are also found in migrating birds, suggesting that the some of the new 2005 polymorphisms literally flew into the area in the fall of 2004.

The analysis of these imported sequences is limited by an incomplete database.  There are still no human 2005 sequences at Genbank or Los Alamos, and the new avian sequences from Qinghai Lake are also not available, nor are any 2005 avian sequences from any country outside of Vietnam, even though other countries such as Thailand, Cambodia, and Indonesia have reported significant H5N1 bird flu outbreaks this season.

The three nucleotide deletion in all 10 HA sequences adds additional evidence for the evolution of H5N1 via recombination.  The deletion has been seen previously in China, Hong Kong, South Korea, and Japan, as 2001 in Hong Kong.  The deletion in Vietnam has clearly been placed on a Vietnam backbone, with most of the polymorphisms specific to Vietnam / Thailand remaining on the newly formed genes.  Indeed the Manila report indicated that additional non-public sequences from Laos, Cambodia, Myanmar, and Malaysia formed a distinct H5N1 subgroup (which would have this same backbone), highlighting the importance of the sequence data for grouping the isolates.  Since most of the polymorphisms are acquired via recombination, the changes also point to the origins of the new sequences.

Many of the polymorphisms originate in migratory birds,  The infected birds in Qinghai Lake offer a unique opportunity for efficiently increasing the avian influenza sequence database, which could be coupled with electronic tagging of the birds.

Aggressive expansion of the database will significantly improve the understanding and monitoring of avian influenza in Asia, and this opportunity should not be lost.

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