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Multiple H5N1 Receptor Binding Domain Changes Cause Concern
Recombinomics Commentary
November 10, 2006

Chen said that in 2005 and 2006, the lab had isolated some viruses in waterfowl in southern China which was reported to the Food and Agriculture Organization (FAO) and the World Organization for Animal Health (OIE).

"These viruses all remain steady in gene type and there is no marked change in their biological characteristics," she said.

Chen said there was only one new variant of the virus, which was isolated to north China's Shanxi Province and the Ningxia Hui Autonomous Region at the beginning of this year and has been reported to the FAO and OIE.
The above comments were in response to the recent PNAS paper describing the spread of the Fujian strain of H5N1 throughout southern China and into Laos, Malaysia, and Thailand.  The response from the Harbin facility in China suggested that there had been little change of H5N1 in southern China since 2004 and the PNAS study was "unscientific" because the immunization status of the H5N1 positive birds was not reported.
However, officials at The WHO requested samples from northern China, because there were 404 full or partial HA sequences in the paper, and the new sequences not only showed that the Fujian strain was becoming dominant, but also showed that there were changes in the receptor binding domain of H5.
The receptor binding domain has been closely monitored because H5N1 can grow to high levels in humans and has generated an alarmingly high case fatality rate.  Changes in the receptor binding domain can have a dramatic effect of the ease of transmission to humans and between humans, and changes in the transmission rate, in the absence in changes in the fatality rate, would lead to a global pandemic that would likely dwarf the devastating pandemic of 1918, which was an H1N1 stain formed via recombination between human and swine H1N1.
An easily transmitted H5N1 could be catastrophic because it represents a non-human serotype and has many genetic changes associated with a high lethality rate in chickens and mammals, including humans.
An earlier survey of H5N1 isolates identified a change in the receptor binding domain, S227N, which was associated with an increased affinity for human receptors found in the upper respiratory tract, and a decrease in affinity for avian receptors.  A warning was issued on October 22, 2005 because the Qinghai strain of H5N1 was migrating into the Middle East and donor sequences for the formation of S227N were present in H9N2, which was endemic to the region.
In January, 2006, the first confirmed human H5N1 fatalities involving the H5N1 Qinghai strain were reported in Turkey, and H5N1 isolated from the index case had S227N, who was part of a large cluster  To date there have been four human sequences from Turkey that have been made public, and two have the S227N change.  Human cases were subsequently confirmed in Iraq, Azerbaijan, Egypt, and Djibouti.  Recently, sequences from the Egyptian cases were released, and S227N was also detected in one of the eight sequences, indicating the change was present over a wide geographical region.
The sequences released in last weeks PNAS paper included five isolates from Shantou with a number of changes in and around the receptor binding domain.  Position 227 was changed, but was changed to an R instead of an S.  In addition to S227N, there were changes at position 222 (K222R) and 223 (V223I).  The isolates also had a change at position 214 (V214M).  The clustering of these changes suggested that they were due to recombination, and sequences with K222R or V223I had been reported previously in isolates from northern China and Japan, so the association of both changes in the five Shantou isolates strongly indicated that the sequences had merged via recombination.
Today, sequences from an isolate from Shanxi were released.  As indicated in the quote above, this isolate was distinct from the Fujian or Shantou strains described above.  In addition to a novel HA cleavage site, REGRRKKR, the isolate also had a number of changes in the receptor binding domain, A188E, A189T, T192I, L194I, R220K, K222Q.  Moreover, two related sequences from Hunan had two of the changes found in the Shanxi isolate, T192I and L194I as well as two more changes, D187N and A189E.
These changes highlight the need for a current database and increase concerns of additional changes via recombination.
Thus, although these are small changes, they can have profound affects of the transmissibility of the H5N1.  Moreover, small changes can lead to false negatives in PCR tests because of mis-matched primers.
Therefore, both groups should release full sequences of all eight gene segments and complete sequences on samples which have only been partially sequenced.

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