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Z Genotype in China is Amantadine Sensitive

Recombinomics Commentary

June 22, 2005

>>  But the controls will be too late for the "Z" strain of the H5N1 virus that has spread through southeast Asia. That strain, which has so far killed 54 people and which health officials fear might develop into a human pandemic, is already resistant to the drug.

On 17 June the Washington Post revealed that amantadine has been used in China "since the late 1990s" to control and prevent bird flu outbreaks on chicken farms. It quoted Chinese pharmaceutical executives and veterinarians who said the drug was cheap, readily available and "widely used in the entire country" both to treat outbreaks and for routine prevention, in the same way that antibiotics are commonly used in livestock.

The investigation followed a report in New Scientist, citing flu expert Robert Webster, of St. Jude Children's Research Hospital in Memphis, US. In it, Webster blamed widespread use of amantadine in feed by Chinese chicken farmers for the occurrence of resistant strains of H5N1 since 2003………

It is not clear when or where resistance to amantadine emerged. Henry Niman, an independent commentator on emerging viruses, says all of the H5N1 isolates from Vietnam and Thailand have had two separate mutations that each confer resistance to amantadine. These are the only countries, besides Cambodia, which have had clinical human cases so far. <<

Since the above comments bring up the Z genotype, it is worth reviewing the Z genotype, amantadine resistance, and human infections and fatalities. The Z genotype is defined by a constellation of genes. It became dominant in 2004 and spread across Asia.

However, although the Z genotype is widespread, there are regional differences, so the Z genotype in Vietnam is slightly different than Thailand, and quite a bit different from Z genotypes in Indonesia, Yunnan Province, Shantou Province,  Hong Kong, South Korea, Japan, etc.

Although 2005 H5N1 sequences are still not publicly available at GenBank, media reports describe differences within Vietnam.  Thus, the Z genotype in northern Vietnam differs from the Z genotype in southern Vietnam.

So far all reported H5N1 fatalities attributed to the Z genotype have been in Vietnam and Thailand (and although not available, Cambodia H5N1 is probably also the Z genotype and similar to the Z genotype in southern Vietnam).

Thus, the Z genotype says little about human infectivity or lethality, although there are other genotypes currently circulating.  All recent deaths and human H5N1 infections have been by the Z genotype, but countries other than Vietnam, Thailand, and Cambodia have no reported deaths, althogh they do have birds infected with the Z genotype..

It is much more useful to look at the polymorphisms that distinguish one Z genotype from another.  In Vietnam and Thailand, all Z genotypes are amantadine resistant, with mutations at M2 amino acid positions 26 and 31.  This resistance is relatively rare in the Z genotypes found elsewhere, including China.  The mutation at position 31 is found in a of Z genotype from Guangdong and Indonesia. The mutation at position 26 is only found in Vietnam and Thailand.

The Z genotypes in Thailand and Vietnam however have a number of polymorphisms not found in other Z genotypes, or other H5N1s.  These polymorphisms unique to Vietnam and Thailand are found in mammalian isolates (from humans and pigs) indicating they were picked up via recombination between H5N1 and a mammalian isolate (serotypes H1N1, H1N2, H3N2).  It is likely that the mammalian isolate also generated the amantadine resistance.

The amantadine resistance status of isolates from Qinghai and Xinjiang has not been disclosed, but the media attention to amantadine resistance may signal amantadine resistances in the more recent isolates from western China also.

However, published sequences from China and other Asian nations indicate that amantadine resistances is rare outside of Vietnam and Thailand (and probably Cambodia), and not found in a large number of Z genotypes found throughout Asia in general and China in particular.

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