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Coments On A242T In H5N1 Ferret Transmission
Sequence comparison of viruses from inoculated and contact animals identified mutations at positions 225 and 242 as well as a reversion at position 224 (Fig. 1a and Supplementary Table 5)
The above comments and figure 1a represent the only discussion of A242T in the Kawaoka H5N1 transmission paper in Nature. The study started with two receptor binding domain changes, N224K and Q226L, as noted in figures 1a and 1b above. Passage in ferrets led to the acquisition of N158D, which is also labeled in figures 1a and 1b. Further passage led to the acquisition of T318I, which stabilized the H5 and was in the stalk region near the fusion peptide, and noted in figure 1b.
However, T318I was only found in one of the six ferret pairs exposed to H5 with N158D. The other five pairs had A242S, which produced a glycosylation site on position 240. That change was not tested further, but sequence analysis of the 10 ferrets exposed to T318I identified A242T in 9, although this high frequency is only listed in Supplementary Table 5, as noted above. The creation of the glycosylation site at position 240 by A242S or A242T is not mentioned, even though two different acquisitions creating the 240 glycosylation site were found in H5 transmitting in ferrets.
Moreover, the paper claims that three of the four positions (N224, Q226, T318) are “strictly conserved among H5 HA proteins isolated since 2003” which is false. N224K has been found in Egypt in 2010 (A/duck/Egypt/10185SS/2010) and in Vietnam in 2007 (A/Muscovy duck/Vietnam/NCVD-11/2007), while T318I has been found in China in 2005 (A/mallard/Xuyi/10/2005, A/spotbill duck/Xuyi/18/2005). In contrast N158D is common in clade 2.2, including the egret H5 (A/egret/Egypt/1162/2006) used by CDC in their H5N1 transmission paper in Virology. Moreover, all clade 2.2 human cases have abolished the glycosylation site at position 158 via N158D, T160A, or both, except for one case in Egypt, Egypt/3300-NAMRU3/2008. However that case is clade 2.2.1 F and has A242T, which is also in most recent clade 2.2.1 F isolates in Egypt.
Thus, although the transmitting H5 in the Nature study has a loss of a glycosylation site at position 158 and the gain of a site at position 240, the H5 circulating in Egypt has one or the other, but not both.
However, the co-circulation of N158D and A242T in Egypt raises concerns that acquisition of both changes via recombination (as seen in PB1 and PB2) will impact H5 transmission in mammals, including humans.