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H5N1 N158D Is Missing Link for Human Transmission Studies
Recombinomics Commentary 20:15
April 4, 2012

he isolated viruses with two mutations in HA — N224K and Q226L — that could stick to receptors in human tracheal cells.

Kawaoka noticed that one of the ferrets he infected had especially high levels of virus in its nose. These viruses had picked up a third HA mutation — N158D — and could now spread between neighbouring ferrets. Kawaoka found that two of six healthy animals picked up infections from neighbours they had no contact with. Along the way, the virus acquired a fourth mutation — T318I.

The above comments describe the H5 changes in the clade 2.3.4 sequence from Hanoi (A/Vietnam/HN31604/2009) used in the Nature paper by Kawaoka.  Media reports have noted the presence of N158D in recent human clade 2.2 cases in Egypt, but N158D was present in the initial wild bird sequences from Egypt, including the H5 sequence used by the CDC (A/egret/Egypt/1162/2006).  Moreover, most clade 2.2 H5 sequences from Egypt do not have a T at position 160, so position 158 is not a glycosylation site, so the presence of N or D is not a glycosylation factor.

However, T is present at position 160 in the clade 2.1 sequence used by Fouchier (A/Indonesia/5/2005) so it is likely that this change was also found in the sequences from H5N1 collected after 10 passages in ferrets.  Moreover, since N158D is also in the CDC clade 2.2, the four matches with Fouchier would be three HA changes (N158D, Q226L, and G228S), as well as PB2 E627K.

Thus, all three studies had N158D and Q226L as well as a PB2 that has been adapted to mammals.  G228S was used in the CDC and Fouchier studies, and each study had one or two unique changes (CDC had Q196R, Kawaoka had N224K and T318I, while Fouchier had an undisclosed acquired change.

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