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There's no reason to suspect that further reassortment happened with avian viruses. In fact, currently we have a pandemic H1N1 virus which is antigenically similar to a seasonal H1N1 virus but contains gene segments most closely related to another seasonal subtype H3N2. All three of these viruses currently co-circulate in humans. There is no reason to suspect that further reassortment will can not happen with these viruses. In fact this is a major worry that researchers are monitoring (as well as a million other worries). Who knows what will be circulating in 30 years and how they'll be related to say California/04/2009
The phylogenies and date estimates, however, do suggest that prior to the emergence of the 1918 virus their was reassortment and the gene segments may not have been introduced as a single intact particle.
This might be the best idea we get of how the 1918 virus was generated. I suspect that ideas surrounding the generation of the 1918 virus will always be contentious.
BM/1918 is only one virus in a population and there is no reason to suspect that this was typical of those circulating. The search for this virus did not look to sample the diversity of viruses circulating at that time, but rather to search for the most lethal example. In Brevig Mission I believe the virus was extremely fatal and all but three people died (my memory might be wrong on the number of survivors).
There are several 1918 isolates and all are virtually identical.
... In fact, currently we have a pandemic H1N1 virus which is antigenically similar to a seasonal H1N1 virus but contains gene segments most closely related to another seasonal subtype H3N2.....
I'm sorry, but which seasonal H1N1 are we talking about here? From every indication, the current Swine Flu is not antigenically related to seasonal flu. In fact, the closest we can come to similarities is that the Swine Flu HA segment is related to the old 1918 HA segment that has been resident in swine for the last 90 years. In the human population this HA was relplaced by H2 in 1957.
It has become almost common wisdom that the virus that caused the 1918 flu pandemic was an avian strain introduced into the human population shortly before the pandemic erupted. But a new study disputes that hypothesis, arguing instead that genes of the 1918 virus had circulated in mammalian hosts, most likely pigs and humans, for several years before 1918.
The origins of the 1918 virus, which is estimated to have killed at least 20 million people, are still controversial. After painstakingly piecing together the genome of the extinct strain, a team led by virologist Jeffery Taubenberger, then at the Armed Forces Institute of Pathology in Washington, D.C., concluded in 2005 that the virus most closely resembled viruses of avian origin; the team suggested it had become transmissible between humans after a couple of key changes
The above comments on the recent PNAS paper as well as the Nature paper in 2005 provides some background on the data supporting a human / swine origin of 1918. The sequence of a 1917 avian isolate clearly demonstrated that avian sequences in 1917 were similar to current avian sequences and easily distinguished from mammalian sequences, such as pandemic 1918 H1N1, seasonal H1N1 and swine H1N1.
The Nature paper of 2005 identified 10 polymorphisms which were said to be pandemic -specific because they were in the 1918 pandemic sequence but not avian sequences. However, these markers were simply mammalian markers and were not only in the H1N1 1918 pandemic sequence but also in seasonal H1N1 and swine H1N1. Thus, the markers did not identify changes that created a pandemic strain, but instead provided additional data supporting a human / swine origin of 1918, as had been seen from phylogenetic analysis.
The swine origin is also supported by the recent Nature paper showing that sera from patients alive in 1918 had <a rel="nofollow" href="http://www.recombinomics.com/News/07130901/H1N1_2009_1918.html">antibodies</a> that not only saw the 1918 pandemic H1N1 strain, but also the current 2009 pandemic strain which is a swine H1N1. Thus, both the antibody data as well as phylogenetic analysis support a mammalian (human and swine) origin of 1918.
However, <a rel="nofollow" href="http://www.recombinomics.com/presentations.html">detailed analysis</a> of the 8 gene segments of the 1918 virus show that it is a recombinant with alternating blocks of swine and human polymorphisms. In fact approximately 90% of the polymorphisms in each of the eight gene segments can be found in two parental sequences, WSN/33 representing human H1N1 and swine/Iowa/15/1931 representing swine H1N1. Although there are some avian polymorphisms, the vast majority of polymorphisms is mammalian and can in fact be found in two isolates from the early 1930's.
These data have important implications for the current pandemic strain, because it is a swine H1N1 which can efficiently transmit in humans. It has spread throughout the human population worldwide, and now is in position for further adaptation to human host via recombination with seasonal H1N1, which is well adapted to humans.
There are several obvious candidates in seasonal H1N1 which could significantly impact swine H1N1. One of the 10 markers identified in the 2005 Nature paper was PB2 E627K. This polymorphism is in virtually all influenza A seasonal flu isolates. It allows for most efficient replication at 33 C, which leads to upper respiratory infections and a preference for seasonal spread, when cold temperatures keep the human nose close to the optimal temperature for E627K. In contrast, the avian version, E627, allows for most efficient replication at 41 C, the body temperature of birds. Since the swine H1N1 PB2 is avian, it has E627, which may lead to less efficient transmission in the winter, but higher transmission in the summer, and associated replication the lower respiratory tract. E627K was reported in <a rel="nofollow" href="http://www.recombinomics.com/News/06180901/H1N1_Swine_E627K.html">one isolate</a> in Shanghai but was only found in the sequences from the original sample as well as the first clone. The second clone had reverted back to E627.
Another potential acquisition from seasonal H1N1 is H274Y. Although this isn't a mammalian specific polymorphisms, it is present on almost 100% of seasonal H1N1 and has a history of jumping from one genetic background to another. It has been reported in three pandemic swine isolates, including a patient traveling from <a rel="nofollow" href="http://www.recombinomics.com/News/07030901/H274Y_HK_SF.html">San Francisco to Hong Kong</a> who had not received oseltamivir, raising concerns of a fit pandemic H1N1 with H274Y. Moreover, this isolate and other related isolates without H274Y also have a receptor binding domain change D225E, which may be important in establishing dominance via genetic hitching. A change at the same position, D225N, was associated with the establishment of H3N2 seasonal flu with adamantane resistance, S31N.
Thus, the movement of swine H1N1 into the human population creates the environment for rapid adaptation to human hosts and the acquisition of key polymorphisms from seasonal H1N1, which could cause significant problems in the upcoming months.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
I'm sorry, but which seasonal H1N1 are we talking about here? From every indication, the current Swine Flu is not antigenically related to seasonal flu. In fact, the closest we can come to similarities is that the Swine Flu HA segment is related to the old 1918 HA segment that has been resident in swine for the last 90 years. In the human population this HA was relplaced by H2 in 1957.
I'm not saying that these different subtypes are antigenically cross-reactive. But both of these molecules are H1 and N1 subtypes. they have related evolutionary histories, even if this history is 90+ years removed, and they have similar shapes. Seasonal H1N1 from 2008 is not cross-reactive with seasonal H1N1 from 2000. But they are both related.
wherever it (1918 panflu) had come from, originally it was in birds, as all flu-A.
Whether it went into mammals 1918 or 1890, doesn't matter so much.(---edit--- for this analysis)
There should still be some bird-sequence showing it, being closer to
~1930s-sequences than to BM/18. (if that 1930s sequences did not
directly come from BM/18 as the paper suggests)
BM/18 is not so unique. We have 3 viruses from 1918 and one from 1919.
Partial sequences only, but they coincide with BM/18.
Actually, it does matter. Taubenberger et al suggested that this virus emerged in the human population as an intact particle from the avian gene pool directly shortly before the 1918 pandemic. The analysis in this paper and your own analysis suggest that these viruses did not emerge simultaneously. If it wasn't simultaneous introduction of genes then it was sequential introduction with reassortment.
The 1919 goose influenza sequence is phylogenetically distantly related to the pandemic.
You suggest the pandemic strain had died and some unnoticed
seasonal strain did take over ? Any example that this ever happened ?
I don't think it's impossible. The phylogenetic evidence suggests that these viruses (1918, classic swine, seasonal H1N1) are all different viruses. The date estimates suggests that these all co-circulated. If I can think of better evidence I'll let you know.
Local differences of the strain are presumably small, as was seen in other pandemics.
H3N2 did reassort a couple of times with segments from old H2N2 between 1968-1972,
though. But not many differences in the single segments.
The seasonal diversity of H1N1 and H3N2 is high enough to need new vaccines annually. There is no reason to suggest that local diversity would be lower. What pandemics are you referring to? I'm not sure I understand what you are suggesting here. Could you clarify?
I'm not saying that these different subtypes are antigenically cross-reactive. But both of these molecules are H1 and N1 subtypes. they have related evolutionary histories, even if this history is 90+ years removed, and they have similar shapes. Seasonal H1N1 from 2008 is not cross-reactive with seasonal H1N1 from 2000. But they are both related.
“Here we provide the first evidence that seasonal H1N1 viruses
were not derived directly from BM/1918 but co-circulated during
the pandemic. This evidence may be relevant to the current
emergence and potential pandemicity of swine-derived H1N1
viruses in humans (1).”
Can we interpret this to disagree with “experts” advice that those of us born before 1957 have some protection against the novel H1N1, because of our exposure to the earlier H1N1?
-------------------------
Regarding the “BEAST” - can this system be aimed “forward” to look at the current pandemic & derive some information that would assist in reducing severe illness and death? (e.g., some data regarding choice of an appropriate anti-viral therapy)
If they had strategic samples could the system perform a “forward-analysis”?
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
my argument above that there should be birds to test the
hypothesis was flawed, I edited it.
I'm thinking about other ideas to test it
(that WS/33 and SW/31 and others did not descend from BM/18
in some segment)
All previous known pandemics were caused by one new virus
which was introduced and after some years this virus killed
previously existing human flu-A viruses.
With the ferret studies showing that the pandemic strain replicates deeper in the lungs and is harder to detect in nasal swabs than the seasonal strain, I'm thinking that the 41 degree replication is the reason. Patients immediately get a high fever which would normally ward off the seasonal strain, but actually works against the patient with this strain which can replicate most effectively at 41 degrees C. Probably younger patients are able to mount a higher temperature which is one reason they are more likely to succumb as they are simply making their lungs more hospitable for the virus to replicate. My guess is that if the pandemic strain picks up the 33 degree gene it will be less severe.
Also, there were reports that patients cared for outdoors fared much better than those treated in the hospitals in 1918. Some people speculated that this was due to Vitamin D exposure, but perhaps these people were breathing in colder air which lowered the temperature in the lungs just enough to slow the virus replcation. Kind of like croup can be relieved with cold air.
my argument above that there should be birds to test the
hypothesis was flawed, I edited it.
I'm thinking about other ideas to test it
(that WS/33 and SW/31 and others did not descend from BM/18
in some segment)
All previous known pandemics were caused by one new virus
which was introduced and after some years this virus killed
previously existing human flu-A viruses.
Phylogentic analysis can be done on each gene segement and there is NO doubt that all 8 gene segments came from recombination between swine H1N1 and human H1N1 (denying this is along the same lines as the avian origin, hocus pocus to maintain a hypotheses that is DOA - the DATA are VERY clear).
Also, there were reports that patients cared for outdoors fared much better than those treated in the hospitals in 1918. Some people speculated that this was due to Vitamin D exposure, but perhaps these people were breathing in colder air which lowered the temperature in the lungs just enough to slow the virus replcation. Kind of like croup can be relieved with cold air.
1918 virus had E627K (human version that grows best at 33 C).
Phylogentic analysis can be done on each gene segement and there is NO doubt that all 8 gene segments came from recombination between swine H1N1 and human H1N1 (denying this is along the same lines as the avian origin, hocus pocus to maintain a hypotheses that is DOA - the DATA are VERY clear).
Phylogenetic analysis can not detect the recombination that you've described in other posts. If you truly believe that you can, then I realise that the issue is not one where you have your own agenda, but rather you don't understand the methods you're using
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