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HA S227N and PB2 E627K In Fatal H5N1 Cambodia Case
Recombinomics Commentary 11:00
January 23, 2012

A man in southwest China who contracted the bird flu virus died on Sunday, health authorities said, the second human death from the virulent disease in the country in just under a month.

The news comes after neighbouring Vietnam, Cambodia and Indonesia also reported deaths from avian influenza

The above comments note the recent increase in fatal H5N1 cases and clusters in southeastern Asia.  Although sequences have not yet been released for any of the above cases, recently released sequences from 2011 Cambodia cases include A/Cambodia/V0606311/2011, which is the most recent 2011 sequence from Cambodia, where all 8 reported cases for 2011 were fatal.  Clade 1 continues to circulate in southeast Asia, including the above sequence, which has HA S227N and PB2 E627K.  Both are these changes are likely to be among the 5 changes in 2 genes linked to aerosol transmission of H5N1 in a ferret model, which has been censored by Nature and Sciences per recommendations by the US NSABB, even though 4 of the 5 changes have also been found in a single published sequence, raising serious concerns about the understanding of influenza evolution by the NSABB board or the understanding of the mission of Nature and Science by editorial boards of the journals.

Both S227N and PB2 E627K are well known changes associated with increased transmission of H5N1.  PB2 E627K was present in several of the H5N1 cases in Hong Kong in 1997, the first reported human H5N1 cases.  It was also present in the only reported H7N7 human fatality associated with the outbreak in the Netherlands in 2003.  The Kawaoka lab, which submitted the censored paper to Nature has published extensively on E627K in H5N1 and is likely among the changes included in the ferret studies.

Similarly, S227N has also been extensively studied and cited.  A survey of H5N1 sequences linked to enhanced binding to human 2,6 gal receptor identified S227N in two isolates from Hong Kong, A/Hong Kong/212/2003 and A/Hong Kong/213/.2003 as the best candidates for increased binding to 2,6 gal receptors, (abundant in the upper respiratory tract of humans) and decreased binding to 2,3 gal receptors (abundant in lower respiratory tract of humans).  These sequences were from a familial cluster involving the death of one child in Fujian proveince followed by the identification of the above two sequences from her brother and father, who returned to Hong Kong (where the father also died).

Concerns regarding these two changes increased when H5N1 was identified in long range migratory birds in the spring of 2005 at Qinghai Lake in central China.  A novel sub-clade (2.2) was identified and reported in Nature and Science.  The sequences had E627K, which had been previously seen in human seasonal influenza, but not avian H5N1. 

Moreover, the clade 2.2 HA sequences could recombine with H9N2 in poultry in the Middle East, leading to an October 22, 2005 prediction and warning that the migration of clade 2.2 would lead to human cases.  The first clade 2.2 human case was from Turkey and confirmed in early 2006.  S227N was identified in the HA sequence.  Virtually all confirmed H5N1 cases were found in clusters, and two of the four sequences from Turkey had S227N (and the frequency was likely to be higher because S227N is at higher concentrations in the human upper respiratory tract, while the sequences from Turkey, including the sister of the index case, were from the lower respiratory tract.  Thus, although the S227N was not reported in the sequence from the lower respiratory tract of the sister of the index case, it was likely in the upper respiratory tract when she was infected by her brother.

Thus, all of the clusters in Turkey, Azerbaijan, and Iraq had PB2 E627K, as well as receptor binding domain changes that include S227N or changes at positions 186 and/or 196, which are also candidates for the five changes linked to aerosol transmission in a ferret model.

In addition to the presence of S227N in Turkey (and Egypt) clusters and cases, S227N was identified as quasi species in fatal cases in Thailand in a prior publication.  Three cases were described in detail, and although S227N was not identified is lung  (lower respiratory tract) sequences, S227N was found in samples collected from the upper respiratory tract or intestines of all three patients.  Moreover, the presence of S227N in clade 1 patients in Vietnam almost led to the declaration of an H5N1 pandemic in 2005.

Moreover, a recent study that selected in vitro changes linked to enhance binding to 2.6 gal receptors, also identified S227N as one of the selected receptor binding domain changes.

Thus, the reporting of HA S227N and PB2 E627K in the most recent sequence  from fatal H5N1 cases in Cambodia raises concerns of recombination with clade sequences circulating in the area, including the recent sequence from Shenzhen, which had multiple receptor binding domain changes, including S227R.

The censoring of the five changes submitted to Science and Nature, even though four of the five sequences have already appeared in a prior published sequence, continues to be hazardous to the world’s health.

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