- Virus from one of the patients shows mutations at the
receptor-binding site. One of the mutations has been seen previously in
viruses isolated from a small outbreak in Hong Kong in 2003 (two cases,
one of which was fatal) and from the 2005 outbreak in Viet Nam. Research
has indicated that the Hong Kong 2003 viruses bind preferentially to human
cell receptors more so than to avian cell receptors. Researchers at the
Mill Hill laboratory anticipate that the Turkish virus will also have this
- The above comments from the WHO update strongly indicate
that the polymorphism found in the isolate from the fatal case in Turkey
is S227N (also called S223N using H3 numbering). The polymorphism lead
to an increased affinity for human receptors and a deceased affinity for
avian receptors. Since the same change in receptor binding affinity is
expected from the Turkey isolate, the change would be S227N.
- H5N1 has been evolving by capturing mammalian polymorphisms
via recombination. The HA wild bird sequence was used to identify donor
sequences that would allow S227N to be created. All of the donor sequences
were in the HA of H9N2 isolates and all recent sequences were from the
Middle East. Since H5N1 had not been previously reported to have been
in the Middle East, the wild bird H5N1 would have a unique opportunity
to acquire this polymorphism which was not found in prior wild bird sequences
tracing back to Qinghai Lake. This acquisition would therefore be likely
to happen when the H5N1 migrated into the region surrounding the Middle
East where H9N2 was endemic.
- This acquisition increased the efficiency for human receptors,
resulting in the first reported human infections by H5N1 wild bird sequences
migrating toward the west. Such cases were reported in Turkey and the
large number of cases and increased size of familial clusters indicated
transmission to humans was more efficient than had been seen previously.
In additional, there have now been several reports of infection in young
brothers tossing a dead bird or playing with gloves used to carry dead
birds. These are more examples of increased efficiency. In the past,
none of the H5N1 cullers in southeast Asia were reported positive for H5N1.
Now in addition to the young children, there are reports of soldiers developing
symptoms after handling infected pigeons.
- The latest results indicate H5N1 continues to acquire
mammalian polymorphisms via recombination, not random mutation, and these
acquisitions are leading to more efficient transmission of H5N1 to humans.
- Fixing Of Human Polymorphisms In H5N1 In Wild
- By Dr. Henry L. Niman, PhD
- Genetic and antigenic analyses have shown that, compared
to previous H5N1 isolates, 20042005 isolates share several amino acid changes
that modulate antigenicity and perhaps other biological functions. Furthermore,
our molecular analysis of the HA from isolates collected in 2005 suggests
that several amino acids located near the receptor-binding site are undergoing
change, some of which may affect antigenicity or transmissibility. For
example, an isolate (VN/JP12-2/05) showed a change from serine to asparagine
at position 223 of the HA1 (S223N) that may affect receptor-binding specificity.
- The above comments from a WHO report in Emerging and
Infectious Diseases adds some additional information regarding the S227N
(also called S223N) poymorphism found in an isolate from a fatal Turkish
case, but specifics are lacking. The WHO report on the Manila meeting
in May, 2005 mentioned changes in positions near the receptor binding
domain for northern Vietnam isolates, but did not give details. The data
in the table associated with the above comments indicates the S227N in
Vietnam was only found in human isolates.
- This species restriction monitors another change, PB2
E627K, which was also limited to mammalian isolates prior to Qinghai Lake
in May, 2005. In Vietnam, Thailand, and Hong Kong, this change was only
found in mammalian isolates and was associated with poor outcomes. However,
it was detected in all 16 wild bird isolates from Qinghai Lake and appears
to be fixed in the migratory bird population, because all subsequent isolates
have had the change. This change is of concern because it allows H5N1
to grow efficiently at 34 C, the temperature of a human nose in the winter.
- The large number of cases and clusters in Turkey suggest
S227N has also become fixed in the bird population, although the wording
in the WHO announcement is somewhat unclear on the number of changes found
in the receptor binding domain. The description indicates one change is
S227N, but no details are given for additional changes.
- The composition of the 2005 isolates from Vietnam are
also unclear, because none of the sequences have been made public, even
though the above isolate was described in a peer reviewed journal, which
usually requires sequences be made pubic.
- The acquisition of S227N was predicted based on donor
sequences present in H9N2 in the Middle East. The presence of H5N1 in
migratory birds allowed for dual infections involving H5N1 and H9N2 in
the Middle East, which may have been due to the expected recombination.
The fixing of S227N in the bird population is cause for concern.
- The two isolates from the Hong Kong patients in 2003
did not have the PB2 E627K, so the human isolate from Turkey may be the
first example of H5N1 with both HA S227N and PB2 E627K.
- Moreover, both changes may now be fixed in H5N1 in birds,
which moves H5N1 on step closer toward sustained human-to-human transmission.