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H5N1 Destroys Basic Tenets of Influenza Genetics
Recombinomics Commentary
May 18, 2005
WHO has released details about the genetic changes found in the 2005 H5N1 isolates. The data in the report should destroy the two basic tenets of influenza genetics: drifts via random mutations and shifts via reassortment. Last year WHO press releases offered reassurances that no human genes were found in the latest H5N1 isolates. Since flu contains eight separate genes, reassortment occers when two viruses infect the same cell and the new virus is composed of a constellation of genes derived from both parental sets. This reassortment does not create new genes, it just puts together new combinations of genes.
However, H5N1 has evolved without reassortment with human genes. In 1997 it killed humans in Hong Kong with 8 avian genes. In 2003 it again killed humans in Hong Kong with 8 avian genes. In 2004 it killed humans in Vietnam and Thailand with 8 avian genes. In 2005 it killed humans in Vietnam and Cambodia with 8 avian genes.
For H5N1 to become a true human pandemic virus it needs to transmit human-to-human more efficiently. The H gene drives this transmission. However, swapping H5 for the human H1 or H3 genes would create a H1N1 or H3N1 virus and humans have antibodies to H1 and H3, so it would not be much of a pandemic virus. To create a real pandemic, influenza doesn't swap its H genes, it changes its H gene.
The 1918 pandemic was caused by H1. 1957 pandemic was caused by H2. 1968 pandemic was caused by H3. The 2005 pandemic is caused by H5.
However, H5N1 is going to achieve efficient human-to-human transmission by changing the H5 gene receptor binding domain. Conventional flu genetics rely on random mutations to change genes slowly via genetic drift. The latest WHO update uses the term frequently to describe the small differences between the 2004 and 2005 isolates. This is thought to arise via random mutation created by frequent errors made by the flu replication complex. These random errors cause genetic drift.
Errors are made, but new errors emerge very infrequently. Most of the changes seen in flu isolates on an annual basis are not new errors, but recycled old errors (mutations).
The recycled old errors create new genes and the mechanism is recombination. Thus, the loss of an amino acid in HA in 2005 H5N1 in northern Vietnam is not a new mutation. It is an old mutation that was identified in 2003 isolates from Hong Kong and Yunan in China, and then seen again in 2004 isolates from Yunan and Guangzhou.
Although the 2005 bird flu sequences have not been made public, the new 2005 genes are largely generated via recombination, because that is how H5N1 and all influenza A viruses evolve..
The new data on the 2005 will show more evolution via recombination. This recombination will be driven by dual infections and the evolution rate will be dependent on the gene pool population and diversity.
Because of the large number of asymptomatic infections, the number of dual infections has increased. This in turn has generated more diversity. Thus, H5N1 in northern Vietnam is distinct from H5N1 in southern Vietnam, and the isolates in Southeast Asia are distinct from isolates in Indonesia, China, South Korea, and Japan. Most of the 2004 and 2005 isolates are the Z genotype, which is defined by reassortment (they all have the same constellation of genes), but only those with further gene changes are linked to reported H5N1 fatal human cases.
The gene changes are all driven by recombination, which simply recycles old mutations and mixes and matches pieces of genes to create new genes.
H5N1 continues to recombine and evolve, as agencies and governments issue press releases on false negatives, and other non-events such as the lack of reassortment with human genes.
A great deal of time has been wasted on drifts (new mutations) and shifts (reassortment) that play a minor role in rapid influenza evolution.
H5N1 evolves rapidly via recombination, which generates drifts and shifts that are biologically meaningful and hazardous to the world's health.
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