Paradigm Shift Intervention Monitoring
twitter
Commentary
Egypt A242T
Raises H5N1 Transmission Concerns
Recombinomics
Commentary 16:15
May 17, 2012
The above discussion is from the revised Kawaoka Nature paper. The comments discount the natural circulation of three of the four changes described in the paper and claim that only N158D is commonly identified. However, 2 of the 3 which are said to be “strictly conserved” since 2003 have been reported in Egypt (N224K), Vietnam (N224K), and China (T318I).
The absence of any discussion of the acquired glycosylation site at position 240 due to A242T or A242S is glaring. Sequencing of H5N1 from ferrets infected with N224K, Q226L and N158D identified A242S in 5 of the 6 pairs. One pair had T318I and that acquisition was added to the three changes cited above to directly or indirectly infect additional ferrets. 9 of the 10 isolates from those ferrets had A242T (as detailed in Supplementary Table 5). Both changes at position 242 created a glycosylation site at position 240, which is common in clade 2.2.1 F isolates collected since 2009 in Egypt or Israel.
Clade 2.2.1 F was identified in vaccinated flocks in Egypt and one human case (Egypt/3300-NAMRU3/2008) has been identified. That case was one of the first isolates with A242T and it also had Q196K, which is closely related to one of the receptor binding domain changes, Q196R, which was used in the CDC H5N1 transmission paper. Q196K is frequently detected in recent clade 2.2.1 F sequences.
The other major clade currently circulating in Egypt is clade 2.2.1 G, which has N158D, which abolishes the glycosylation site at position 158. This change was also present in the egret H5 (A/egret/Egypt/1162/2006) used by the CDC and as noted above, is widespread in clade 2.2. There are currently more than 100 public H5 sequences from clade 2.2 cases (in Turkey, Azerbaijan, Iraq, Egypt, and Bangladesh) and all but one have abolished the glycosylation site at position 158 (either via N158D, S160A, or both). The one case with glycosylated 158, , is clade 2.2.1 F, which also has glycosylated 240.
Thus, while the ferrets transmitting H5 in the Kawaoka study have lost the 158 glycosylation site and gained the 240 glycosylation site, all human clade 2.2 cases either have lost glycosylation at both sites, or gained glycosylation at both site.
However, recently released sequences from clade 2.2.1 F poultry isolates in Egypt have acquired H1N1pdm09 sequences in PB1 and/or PB2 via recombination, raising concerns of additional acquisitions from H1N1pdm09, such as the two changes linked to variant cases in the United States. All 21 US cases since 2010 (19 H3N2v, 1 H1N2v, 1 H1N1v) have either PB1 E618D or MP from H1N1pdm09, which is linked to human transmission. Moreover, recombination between co-circulating H5 could generate the 158/240 glycoylation pattern identified in H5 transmitting in ferrets.
This analysis is limited by the failure of NAMRU-3 to reelase human sequences since the spring of 2010, and the small number of recent H5N1 internal gene sequences in Egypt or Israel.
Recombinomics
Presentations
Recombinomics
Publications
Recombinomics
Paper
at Nature Precedings