Migration Route of Tamiflu Resistance to Scandinavia
Recombinomics Commentary 04:14
March 24, 2008
The recent sudden appearance of H274Y in H1N1 seasonal flu has raised questions that seriously challenge the basic tenets of influenza genetics, which use selection of random mutations generated by copy errors as the mechanism of genetic drift. As has been noted, the Tamiflu resistance has been most prevalent in Norway, where use of Tamiflu is not common. Moreover, the H1N1 with H274Y is evolutionarily fit and linked to multiple introductions.
However, the genetic change in H1N1 seasonal flu, has been reported previously in H5N1 patients in Vietnam treated with Tamiflu, including at least one patient treated with a prophylactic dose of Tamiflu in Vietnam in 2005. That was followed by the appearance of the same mutation in H5N1 in wild birds in Astrakhan in the fall of 2005.
The sequence of the Astrakhan isolates shared polymorphisms with H5N1 in Denmark and Sweden and had also acquired human polymorphisms. Thus, a pathway from Vietnam to wild birds in central China (Qinghai Lake), Mongolia (Erhel Lake), and Russia (Chaney Lake) in the spring and summer of 2005, followed by migration to Astrakhan (Volga Delta) in the fall of 2005, followed by Scandinavia, is established by H5N1 analysis of public sequences.
This migration of individual polymorphisms is easily explained by recombination which demonstrates movement geographically as well as genetically.
However, the influenza experts who were startled by the sudden appearance of Tamiflu resistance in seasonal H1N1 isolates in Europe have actively ignored recombination as a mechanism underlying genetic drift. Genetic efforts have focused on reassortment, which involves the exchange of whole gene segments in hosts infected by two or more influenza genomes. Similarly, the movement of H5N1 by migratory birds has been discounted, even though all H5N1 west of China has been the same clade 2.2 subclade first identified in wild birds at Qinghai Lake in China in the spring of 2005.
The denial of homologous recombination and the movement of such recombinants by migratory birds continues to endanger the world’s health. Sequences which define the migration routes are still being withheld by the public health agencies that are funded to improve the world’s health, and many of the hoarding institutes are the WHO consultants who collect the samples from other public health agencies and then hoard the sequence data.
The Tamiflu resistance in NA in Astrakhan was promptly reported by health agencies in Russia in 2005. At that time countries in western Europe, the Middle East, Africa, and south Asia were denying any H5N1. After patients began to die from H5N1 in Turkey in early 2006, countries in all of the above regions suddenly “discovered” H5N1 in subsequent months in early 2006. All of the isolates were the same Qinghai strain of H5N1, and in many countries, the H5N1 was only found in wild birds. However, many of the sequences from early 2006 still have not been released.
The Astrakhan H5N1 was related to a subclade that has been reported in northern Germany, Denmark, Sweden, and Scotland. Full sequences have been released from Denmark and recently the sequences from the one isolate from Scotland were released. Sequences from only one gene have been released from the isolates in Sweden, and only HA and partial NA sequences have been released from the isolates in northern Germany, even though all of these isolates were collected well over two years ago, in early 2006.
Some of these sequences were held in a WHO private database which can only be accessed by WHO consultants. The laboratories focus on reassortment and actively ignore recombination and withhold the sequences which provide additional support for recombination and the tracing of polymorphisms from location to location, which can be used to identify the origins of the Tamiflu resistances as well as hundreds of additional polymorphisms which define genetic drift.
The continued hoarding of sequences, and the active ignoring or recombination and the transport and transmission of these polymorphisms by migratory birds, continues to be hazardous to the world’s health.
Media Links
Recombinomics Presentations
Recombinomics Publications
Recombinomics Paper at Nature Precedings