Emergence and Fixing of Antiviral Resistance in Influenza A Via Recombination and Hitch Hiking
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- Recombinomics, Inc.
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- Date:
- Received 29 January 2009 21:07 UTC; Posted 10 February 2009
- Subjects:
- Biotechnology, Genetics & Genomics, Immunology
- Abstract:
The dramatic rise of oseltamivir resistance in the H1N1 serotype in the 2007/2008 season and the fixing of H274Y in the 2008/2009 season has raised concerns regarding individuals at risk for seasonal influenza, as well as development of similar resistance in the H5N1 serotype. Previously, oseltamivir resistance produced changes in H1N1 and H3N2 at multiple positions in treated patients. In contrast, the recently reported resistance involved patients who had not recently taken oseltamivir. Moreover, the resistance was limited to the H1N1 which had acquired H274Y. Using phylogenetic analysis I show that the fixing of H274Y was due to hitch hiking on a genetic background that acquired key changes from another circulating sub-clade. H274Y jumped from clade 2C (Hong Kong/2562/2006-like) to clade 1 (New Caledonia/20/1999-like) to clade 2B (Brisbane/59/2007-like) which included multiple introductions. Sub-clades that had acquired key changes on the neuramindase and hemagglutinin genes expanded and fixed of H274Y on H1N1. These changes led to the spread of adamantane resistance on clade 2C outside of Asia, followed by the spread of oseltamivir resistance in 2007/2008 and the fixing of H274Y in 2008/2009. The hemagglutinin change, A193T, was a key component and the coincident polymorphism, S193F, was linked to the fixing of adamantane resistance in H3N2. The aggregation of key polymorphisms onto different genetic backgrounds supports a mechanism of homologous recombination between co-circulating influenza sub-clades, and provides a rationale for the prediction of vaccine targets and emergence of antiviral resistance.
Discussion
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6 votes
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4 comments
Yes, the importance of A193T in the fixing of H274Y has been confirmed by recently released sequences by the US CDC, Japan’s NIID, and the WHO regional center in Australia (on deposit at Genbank or GISAID). Virtually all clade 2B sequences with H274Y have A193T, although isolates have subsequently formed three major branches, as seen in the recently released H1N1 HA phylogenetic tree (slide 14).
The acquisition of A193T by multiple H1N1 sub-clades signaled its importance, and the combining of A193T with H274Y created the constellation that led to the fixing of H274Y in H1N1 throughout the northern hemisphere, which will likely be extended to the southern hemisphere in the upcoming weeks.
The predictability of these changes is quite remarkable. The hitch-hiking paper is being updated with the more recently released sequences from this season, which describes the importance of the receptor binding domain changes. Some of these changes are detailed in the HA tree (slide 14) from the CDC, but that tree is not fully annotated.
The emerging H1N1 isolates all have A193T, but each of the 5 newly formed branches is rooted in addition receptor binding changes, and all are at three flanking positions (187, 189, 196). There are two polymorphisms at 187 (N187S and N187D) and 196 (H196R and H196N), as well as four at position 189 (G189A, G189N, G189S, G189V).
The top branch in the CDC tree is labeled with G189A (as well as S145N). These acquisitions are widespread in Asia (including most isolates in Japan, South Korea, and Taiwan) and are associated with vaccine resistance. All five of the first H1N1 isolates from Italy had these acquisitions, and three of the isolates were from patients who had been vaccinated this season. Similarly, Taiwan reported that 70% of the H1N1 isolates there were vaccine resistant. These changes are also in US isolates, but are fairly rare.
The second branch in the CDC tree is labeled with G189V and H196R. All isolates are from the US and this is the dominant strain in the US. However, this sub-clade is also in Japan and was linked to school closings in Sendai last fall, as described earlier.
The third branch in the CDC tree is labeled N187S, but there are actually two sub-clades in this branch. One was detailed in the hitch-hiking paper and has N187S and G189N. These isolates were in South Africa and Australia in the summer of 2008 and are in Kenya in the fall. There are a few isolates in the US. However, a more common sub-clade in the US has N187S and G189S.
The fourth branch in the CDC tree only has two US isolates, and is not annotated. However, this sub-clade is fairly widespread in the US and is also in Argentina. These isolates have N187D.
The fifth branch in the CDC tree has one isolate from China (Jilin), but there are now multiple isolates from Jilin, as well as isolates from South Australia, which fall on this branch and these isolates have H196N.
Thus, ever major branch that has emerged this season has A193T (and hitch-hiking H274Y on NA) as well as at least one adjacent HA change, which is limited to three positions (187, 189, 196).
As described in the paper, the changes for the acquisitions can be found in other H1N1 isolates that are co-circulating with the emerging H1N1, providing additional support for acquisitions via recombination, and for predictions based on such circulating polymorphisms.
The Japan NIH has released a new NA phylogenetic tree of H1N1 this season. Included are nine isolates from 2009, which all map with the major sub-clade in Japan. The tree also includes isolates from South Korea which map to the same dominant branch. HA sequences from these isolates have A193T and the flanking polymorphism of G189A. These sequences are also in a small number of isolates from the US and match the first five H1N1 isolates from Italy, as well as isolates from Taiwan.
Also included are isolates from Japan that were associated with an elementary school in the fall, which matches the dominant H1N1 sub-clade in the US. HA sequences from these isolates have A1893T with G189V and H196R.
Japan NIH also released titers of 18 isolates against ferret reference anti-sera. These data clearly demonstrate significant drift of the recent isolates from last year’s H1N1 vaccine target, A/Solomon Islands/3/2006 (clade 2A). However, last season there was little clade 2A in circulation, raising concerns that the drift was accelerated by a poorly matched vaccine. Although the 18 test antigens represented multiple recent sub-clades, with HA sequences with A193T plus one or two additional changes at flanking positions 187, 189, and 196, all had reductions in titers when tested with the clade 2A reference anti-sera. Two were reduced four fold, but the remainder had reductions ranging from eight to thirty-two fold.
Similar results were generated for clade 2C, which was represented by recent anti-sera against A/Shiga/8/2008. One isolate was reduced four fold while the rest were reduced eight to thirty-two fold. These lower titers help explain the spread of clade 2B in Asia, where clade 2C was widespread last season.
However, reduced titers were also seen for A/Brisbane/59/2007 (clade 2B), although results were more complex. Two reference sera were used. One was directed against Brisbane/59 grown in eggs and like last season, the anti-sera had significant cross reactivity with the reference sera as well as the recent isolates. The mammalian cell isolate however discriminated between the reference sera, especially for clade 2C, where the titer was reduced eight fold. This level of reduction was also seen for four of the test isolates. Three were the dominant sub-clade in Japan, while the other was the dominant sub-clade in the US. These titer reductions support reports of vaccine failures in Asia and North America.
The recent announcement that the H1N1 target for the 2009/2010 will remain unchanged, raise concerns of more vaccine failures next season.
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Niman, Henry. Emergence and Fixing of Antiviral Resistance in Influenza A Via Recombination and Hitch Hiking. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2009.2832.1> (2009)
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Kent Nickell on 10 February 2009 13:18 UTC
This to me is the future of influenza evolution predictions… I think bioinformatic type analysis of various viral genomes will prove very fruitful esp in areas such as influenza where you want to be right on top of these changes for vaccine development as well as changes such as drug resistance, virulence factors etc