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N186K In H5N1 in Azerbaijan Patients

Recombinomics Commentary
December 2,  2006

Recently released human H5N1 sequences from Azerbaijan patients shed additional light on HA changes affecting the affinity of binding to 2,6 gal receptors, which are found in the human upper respiratory tract.  Interest in such changes has been high, since an increased affinity is likely to lead to more efficient human-to-human transmission.  The acquisition of one such change, S227N, was predicted because donor sequences were present in H9N2 in birds in the Middle East and Qinghai H5N1 migrated into the region in the fall of 2005.

S227N was present in the index case for the outbreak in Turkey as well as a second case in Turkey and a case in Egypt.  A recent paper in Nature indicated S227N could synergize with another HA change, Q196R which was present patients from Iraq and or Azerbaijan.  Moreover, another change that increased affinity for human receptor, N186K, was as present in these patients.  However, these changes were not present in the public human sequences from these two countries and the description in the Nature paper was ambiguous.  It was unclear if patients had one or both changes, and it was unclear which changes were in which patients.  The only change in these positions in the public sequences was N186S in the index case for Iraq.  Thus, only WHO consultants who could access the private database could confirm the statements in the Nature paper.

The release of five human H5N1 from Iraq clarified the distribution in Iraq.  All six sequences had N186S and two h
ad Q196R.  The effect of N186S in receptor binding was not described in the Nature paper.  However, this change is only in the human sequences from Iraq.  It was not present in a goose or cat sequence from Iraq.

In addition to the five human sequences from Iraq, four additional human sequences from Azerbaijan were released.  Those isolates are listed below.  Two of the newly released sequences, A/Azerbaijan/001-161/2006 and A/Azerbaijan/011-162/2006 have N186K.

This newly released data are cause for concern.  All of these isolates are in the Qinghai strain of H5N1, which has another mammalian polymorphism, PB2 E627K.  Moreover, a recent isolate from a fatal case in Egypt has M230I.  This is the first reported Qinghai H5N1 with this change.  This change is found in all three circulating human HA's, H1N1, H3N2, and influenza B.  Moreover, this change creates an identity between H5N1 and influenza B at positions 226-230 (QSGRI).

These changes in Qinghai isolates in a relatively small geographic region region are cause for concern.  All of the isolates have PB2 E627K.  S227N has been detected in Turkey and Egypt.  N186K is in Azerbaijan, which is adjacent to Turkey and Iraq, while N186S and Q196R is in Iraq.  Egypt has M230I, in addition to S227N.

Additional combinations are possible because all of these changes are in the Qinghai strain, which can lead to further recombination and acquisition of more than one change in the same host. 

E627K has become fixed in in wild birds with Qinghai H5N1.  Detection of the HA changes has been largely limited to human isolates, although N186S and M230I have been found in H5N1 in birds.  Detection of these changes in birds may be low because of isolation procedures.  Isolation of H5N1 from avian sources involves chicken eggs, which selects against these changes.  Moreover, heterogeneity has been found in human isolates grown on mammalian MDCK cells.  The patient from Vietnam who had both Q196R and S227N did not have either change in two of the three reported clones.  Similarly N186K was in the first sequence deposited from the patient in Thailand, but was absent in the second sequence.  In the examples from southeast Asia, the differential results were reported by the same lab, further highlighting the heterogeneity.

None of these changes have been reported in human H5N1 isolates from Indonesia, although clusters are common.  However, the H5N1 from Indonesia is isolated in chicken eggs by Hong Kong and the CDC, which may limit detection of such changes.

H5N1 has already re-emerged in Egypt where M230I was detected.  Moreover, there have now been reports of three suspected clusters in Sohag.  Although these cluster have not been confirmed, the multiple, clusters in the same region where H5N1 has been detected in poultry remains a cause for concern. More information on the status of the patients, as well as additional sequence data from the region would be useful.

Newly Released
ISDN140057  A/Azerbaijan/001-161/2006(H5N1)  H5N1  2006
ISDN140056  A/Azerbaijan/011-162/2006(H5N1)  H5N1  2006
ISDN140058  A/Azerbaijan/002-115/2006(H5N1)  H5N1  2006
ISDN140055  A/Azerbaijan/008-208/2006(H5N1)  H5N1  2006
Previously Released
ISDN140054  A/Azerbaijan/006-207/2006(H5N1)  H5N1  2006

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