explanation of sequence letter codes
this thread is to continue the discussion about the Indonesian mutation
in the cleavage site from:
http://tinyurl.com/keff6
http://tinyurl.com/muhzf
I’m just waiting for Henry to show us from whence the human strains acquired the Serine in the third position?
The cleavage site is in most of the human H5N1 HA sequences from Indonesia. It has not been described elswhere. Comments on cleavage site evolution and swine H5N1 cleavage sites.
Niman-
Do you consider the Uncharged amino acids, Glycine and Isoleucine, that are found in the third position of 7 of your cleavage sites in the previous table to potentially be intermediate substitutions on the way to another Basic amino acid (R,H,K)?
That is possible, but there are not enough earlier ceavage sites to say for certain.
Niman-
Have you observed or do your recombination rules allow for a two step procedure for the building of a polybasic High Pathogenic cleavage site?
Recombination rules are dictated by sequence homology.
the human body seems to “prefer” RESRRKKR in the Indonesian strain. Why ? Do the RERRRKKR viruses not infect humans or not replicate in humans so well ? Can’t this be tested in cats ?
RERRRKKR is the most common H5N1 cleavage site and is almost all dead patients in Vietnam, Thailand, Cambodia. A milder version in in Vietnam in 2005 lost an R so it was RERRKKR. In China, a K has been lost in human cases, so it is RERRRKR, and the Qinghai strain is GERRRKKR (which is in H5N1 from patients in Turkey, Iraq, Azerbaijan, Egypt).
RERRRKKR was also in the Hong Kong patients in 1997 and 2003.
niman-
Can you give us an simple example of how recombination rules are dictated by sequence homology?
Something straightforward for the average reader like the many examples in your patent application.
Niman-
Do you believe that more basic aminos in the cleavage always make for a more pathogenic strain?
As the Indonesian strain is one less basic than the HK 1997 and HK2003, can you comment on the differences in pathogenicity or other characteristics?
RERRRKKR was HK1997,HK2003
RESRRKKR was Indonesia2005
same length.
I guess, niman is not so happy, that this can’t be used to make a claim about recombination ;-) But I hope he will help us to discuss its reasons and implecations nevertheless. I feel, it could be important and significant to understand the virus better.
anonymous – at 06:48
Of course they are the same length?
My question to Niman concerns the substitution of the Serine for the Arginine, hence the loss of one of the basic amino acids. Serine is uncharged.
We know that the poly-basic cleavage site is frequently correlated with high path strains, but do more basic aminos (7 of 8 like HK) make for a more pathogenic strain than fewer basic aminos (6 of 8 like Indonesia 2005)?
See what I mean now?
Seems counter-intuitive to me? Just looking for Dr. Niman’s thoughts?
I’m not sure about your comment on Dr. Niman’s happiness about recombination here? On this cleavage site, the point is really moot. Recombination cannot be shown in this case due to the dearth of sequences being publicly submitted?
NS1 -at 06:58
OK.I see.
Do we have a list of basic amino-acids ?
Do you have any remote idea, why this S could be more suitable for
mammals in Indonesia ? Is there any similar situation known with
host-switches ?
It seems that high vs. low path. is not so important here from the
virus’ point of view. It can spread even when the host dies.
Or not ? Could this serine be a hint for a version which is
lower path. and thus more successful in some intermediate host (pigs ?) ?
I hope, niman will join the discussion even though it might
not be important for the recombination claim.
Don’t you feel the subject is important and should have been
discussed already ?
anonymous – at 08:19
Amino Acids with side chains having a physiological pH that is Basic - Arginine ®, Lysine (K) and Histidine (H).
These three amino acids are more probable to be located on the protein’s surface because their positive charges categorise them as hydrophilic.
The Serine may not be more suitable and may be an artifact or anachronism from a recombination. Remember, not all genetic acquisition is progressive. Retroprogessive acquistions happen just as frequently, probably more so.
We are only looking her at a few amino acids in one of eight gene segments. The WHO has only released two gene segments. We’d like to see the NS1 segment, along with the remaining five, released.
The virus has no point of view?
The H5N1 virus is spread before the host dies, so transmissibility and pathogenicity are not necessarily inverse functions. The serine could be a hint or it could be a pure artifact.
why can’t we get any comment on this from some expert or whatever ? Why are they all ignoring this ? It looks highly relevant to me and this is known since February at least. Google hits for resrrkkr: http://www.einnews.com/ChinaTaiwanHongKong/newsfeed-China-Taiwan-HK-Forestry (can’t access) they found resrrkkr in Indonesian swine ?
What sort of comment do you want? Or what sort of expert?
are there other examples for such host-specific mutations ?
does it imply adaption to humans ? Does it suggest an intermediate host ?
Can other mutations like tamiflu-mutation occur as easily ? Are studies
being planned to test the mutations (like they did with the receptor
mutations) ?
sort of experts: virologists
Tamiflu and other anti-viral resistence has been observed to form sometimes during the course of treatment, so that’s pretty fast.
Of course, many examples exist for what we think may be host-specific beneficialities in the sequences. The cleavage area that we are discussing here has little to do with host adaptation and is studied typically in relation to pathogenicity.
These changes are not likely mutations. Mutations are random.
Tracking a sequence from one host to another, many times is as simple as matching the sequences from the two hosts (sometimes allowing for known host-specific polymorphisms).
The cleavage area is novel because it has not been previously measured, it’s not on file. So we don’t know if it suggests an intermediate? It’s possible, but without the data, we are all just guessing.
and reporters and politicians and WHO,CDC, etc. should comment. The story had been out since February. Am I the only one who thinks this is important ? More important than just another cluster or just another infected species or just another country ? Isn’t it the sort of mutation, we were looking for all the time ? We had E627K, but it occurred in birds and humans, this one separates birds from humans. It’s out since February, still no comment. WHO ignores it, the media ignore it, fluwiki ignored it, experts ignore it.
alone, the matter of the cleavage site is of little value.
what is all the concern?
why have almost all the birds in Indonesia RERRRKKR and almost all the mammals RESRRKKR ? Please guess ! When we infect birds with RESRRKKR, will it change to RERRRKKR ? When we infect mammals with RERRRKKR, will it change to RESRRKKR ? Is this a first step how the virus adapts to humans ? If yes, what human property (vs.avian) is specific to the R→S change ? We need to know this. I wonder whether they are (secretely,as usual,sigh) testing this.
NS1, the concern is the pandemic, which could kill hundreds of millions.
Something significant is going on, which we don’t understand. Don’t you feel it’s important ? Don’t you feel, it could be key to our understanding of the virus ? Cleavage site or not. We have no reasonable explanation. One of our main problems is, that we can’t predict how the virus mutates and adapts and gains abilities. If we could predict this, we could produce a vaccine in advance. Or maybe even produce a low.path. variant and trigger an anti-pandemic to produce immunity. The cleavage site is particularily important for virulance.
Any attempts at an anti-pandemic strain will likely result in another recombinant once it is in the wild. We can’t exactly predict the activity of the potential recombinants from something that we introduce? We can predict that it will very likely have no effect or make things worse.
THEY are secretly testing everything.
I’m sure that your protocol is being tested in a lab somewhere.
anon-
Would you mind using a name of some sort? There are so many anons and I’d like to be able to keep your posts together so I can study them.
What is your field of expertise?
NS1, no. Concentrate on the arguments, not on the credentials. If it’s valid or reasonable then it’s valid or reasonable independently on the credentials. Despite your name, the HA-gene is usually considered more important. I usually ignore messages hidden in names or signatures.
when we are desparate enough, we will try anything. Maybe even an anti-pandemic strain. I don’t know. But I think we should talk about it now. We should also loosen the ethical constraints on laboratory tests in times like these. Maybe we can test it in a laboratory setting.
I have a natural curiosity about the NS1 gene; I certainly place no level of importance on my moniker relative to the other gene segments? No hidden message is intended.
If I have an idea of your interests, background or professional training, we can certainly have a more informed discussion? Otherwise, I really don’t know where to start?
Some of your questions led me to believe that you have a deep study in this field; others led me to believe that my answers are not registering with you? So, I am confused and don’t really know how to answer you.
Could you at least join the anon## corps and take a number?
Danke.
anon-
Lab conditions do not approximate the wild habitat when we are addressing potential recombination with wild influenza? Your proposed test would yield no relevant results?
The novel cleavage site, RESRRKKR, may or may not be related to pathogenicity, but it serves as a marker for tracing the origin of the infection. Right now WHO and Indonesia maintain that the human cases in Indonesia are caused by H5N1 from poultry. However, virtually all human cases have RESRRKKR, while all reported poultry cases have RERRRKKR, STRONGLY suggesting that the human case are NOT due to infection by H5N1 fom poultry.
Surveillance in Indonesia (and most of the world) is poor. The number of birds infected by H5N1 is very high and an intesive screening campaign of H5N1 positive birds (and swine) in the Jakarta area should have been launched last fall, when human cases began appearing.
THe avian sequence publicly available are listed here.
Niman-
Do you give any significance to the Serine substitution? Have you seen this in other species attributed to any disease characteristic? What are your thoughts on this matter?
niman, so this is significant and important ? How could you miss it the last 3 months ?? Why can’t the mutation occur every time inside the human : RERRRKKR in, RESRRKKR out ? Or RERRRKKR in - no binding,no infection. But (rare) RESRRKKR in - binding ?
anon-
How can you press a question like, “Why can’t the mutation occur every time?
A mutation is defined as a random event. Why would you expect a random event to be repeated at least 11 times?
O have previously summarized the cleavage site evolution.
Niman-
Can you give some interpretation to the Serine?
Although the cleavage site has been used as a cnvenient marker, the human cases form a seperate clade, with many chnages that distinguish the human cases in Indonesia from all other public sequences. The sequences should be released immediately. The sequences would clearly show that the public bird H5N1 sequences were NOT the source of infection in the majority of the human cases in Indoensia.
selection. The random mutation H274Y(NA) did occur in Tamiflu treated children in 10% of cases, although they were infected with a virus without that mutation. Maybe it’s unlikely but can’t similar things happen with RESRRKKR ? Maybe the organ where the swaps are taken can only reproduce RESRRKKR viruses ? Maybe the later growth in chicken eggs or canine cells favours RESRRKKR viruses ?
Right now teh serine is a marker. It as asociated with an extermely high CFR and in the only public sequence, it is also associated with a novel glycosylation site.
RESRRKKR has become fixed in human cases in West Java. It is present in virtually all isolates in 2005 and 2006.
there are other markers to distinguish the human sequences from the avian ones ? How do you know ? That suggests that a lot of H5N1 infections are going on in Indonesia undetected - in whatever host.
anon-
If a polymorphism occurs in 1 of 10 cases consistently, then we are definately not looking at a mutation; a mutation is random?
Niman-
Does this human strain show S227N or any other RBD polymorphisms of significance?
anon, Your question was answered when the human sequence (HA and NA) was made public. Maybe its all just a Martian plot!
Niman-
Most likely its a back-end, Uranal plot.
NS1, can you explain, why the same mutation can’t occur 10 times ? Yes, there would also be many other mutations but RESRRKKR would survive, while the other viruses would die inside the host. niman, from your link I assume that you mean the A90T ? But we don’t know, whether it is also in the other human samples from Indonesia, while we are positive here for RESRRKKR
A mutation by definition is random. Random events do not occur 1 of 10 times except on the 7th planet.
uhh, it does happen with Tamiflu resistance. Maybe I wasn’t clear. Suppose the RERRRKKR-virus enters the human in some place,(lung?) mutates and replicates. Lots of mutations happen : RERRRKKR,REIRRKKR,REDRRKKR, GERRRKKR,RERRRKR,… But in the organ or region where the swap is taken (which?) only RESRRKKR can survive, the other ones are not compatible with the cells in that organ. So the swap will always only show RESRRKKR.
As I sqid earlier, the novel cleavage site is linked to a new clade involving many changes (which are NOT random).
that would be really strange. Are you sure ? How can you know ? A new strain enters Indonesia, kills dozends of people in a year and no one notices where it is coming from … Well, the Indonesians and WHO,CDC should have known this since long then. And they didn’t say anything ??? How will they justify this from the press ? I mean, keeping sequences in a keyword-locked database is one thing but keeping a whole epidemic in some host (swine?) secret with pandemic potential would be another thing !
Anonymous - at 13:10
Not true. By keeping the Sequences from the public, they have the ability to deny that they were able to see this comming. Once brake out of Supstaned H2H2H happens they display the proper shock at it happening. Much the same way Corp of Engineers expressed shock over the levees breaking in NO yet they all knew it could and most likly would happen. You are thinking like a citizen and not a government worker.
anon-
What do you mean? The WHO is keeping everything that they can under wraps? You seem surprised?
One more time. Almost all of the H5N1 sequences from humans in Indonesia form a new clade which includes the public sequence which has many human specific polymorphisms including a novel cleavage site and a new glycosylation site, A90T. These differences are locked up in the WHO database, The sequences were generated independently by the CDC and Hong Kong amd each dataset corroborates the other.
If kept secre, the human polymorphisms do not have to be addressed by Indonesia, the WHO, Hong Kong, or the CDC. The source of the new sequences is not known. The new clade is most closley related to bird sequences from Indonesia and those doing the sequencing can keep saying the sequence differences are due to random mutations. They have gotten away with that line for years, and will continue to use it as long as they are allowed to get away with it.
The differences are quite obvious, and those differences include the novel cleaavage site, RESRRKKR, which was present in the first reported human isolate in 2005 as well as isolates in 2006. These sequences did NOT come from a known poultry source.
Niman-
Would you mind presenting the RBD and discussing significant polymorphisms like S227N and / or any others?
These sequences did NOT come from a known poultry source.
I don’t believe this. They might fail to
find the source of the human infections occasionally, but not
so often and almost regularly. What could have been that
unknown source next to poultry-viruses but not
mixing with them ?
One human sequence has been published. It has several distinguishing polymoprphisms which are in the other huamn sequences, including RESRRKKR, but not in ANY published bird isolates.
This has nothing to do with what you believe, which appears to be based on major misconceptions.
Dr. Niman - I hear you. My husband believes sequences aren’t being released because of bioterrism concerns. Do you think this is true?
GhostRN-
If we were concerned about bio-terrorism, Dr. Taubenberger and his team would never have released the sequences from his work on the 1918 virus?
The sequences aren’t being released for commercial reasons and because the academicians cannot yet explain the genetic acquisition paths without concuring with Dr. Niman’s rules-based recombination theory.
niman, I understood your quote to mean, that _none_ of these 10 or 11 human sequences with RESRRKKR did come from any of the Indonesian poultry sequences with RERRRKKR ? I don’t know about the published one (/5/2005)
But I think that usually there either are some rare poultry sequences with RESRRKKR in the sea of RERRRKKR-sequences which infect the human or the mutation was created inside the human. (or measurement problems). I don’t think there is one large animal-source with RESSRRKKR independent of the poultry and this source permanently infects humans. As I understood, this is what you think. (right ?)
RESRRKKR came from pigs
The sequence have nothing to do with bioterrorism (one of the human sequences is already public).
The origin of the RESRRKKR has not been determined. No poultry with that sequence in the Jakarta area has ben identifed. The change did not happen in humans. It is associated with a number of sdditional changes and has been since the first case in 2005 and through 2006.
Several poultry sequences from West Java have been published. None contain RESRRKKR.
Niman-
It sounds like you are reasonably confident that the Serine substitution was not a polymorphism that occurred inside a human?
NS1…
You stated commercial reasons for the withholding of the sequences… could you explain to a layman please? What is the commercial value of such????
TIA, SZ
The cash cow here is the patent rights for vaccines and publications, diagnostic tests etc. …..
yes, niman,Nabarro,Webster,Osterholm,Oxford,.. where did this polymorphism come from ? Not important enough to make a statement ? All that you find in the media about resrrkkr is from recombinomics=niman. Apparantly no other scientist or reporter considers this anyhow interesting…
There is only one public human sequence from Indonesia.
see the other thread. WHO commented on the new sequences from the cluster, they scanned all 8 segments but didn’t mention what the cleavage site was !
anonymous – at 00:42
WHO commented on the new sequences from the cluster, they scanned all 8 segments but didn’t mention what the cleavage site was !
No they didn’t, that’s true. Releasing the sequences would put this whole discussion to rest. It’s based on whether random mutation vs recombination is an important viral evolutionary tool. WHO doesn’t necessarly accept it is (they may accept recombination but not as an ‘important’ mechanism) and doesn’t look at the data the same way.
This site (Flu Wiki) doesn’t exist to fight Henry Niman’s recombination-as-evolution battle for him. Not all posters agree with niman about its importance, and not all scientists do (maybe most don’t, but I have asked and never gotten a straight answer). I do know CDC now lists recombination in their flu Q&A. But that’s not important that we do or don’t believe Henry. Nor do we have commercial interests at stake. niman’s point is accepted that the only way to deal with the science is to release the data to all interested independent scientists. It’s not just him asking.
Bioterror has nothing to do with it… the US Navy has released what sequences they have under their control and, to my knowledge, so has NIH. Only CDC and WHO have not.
bump. Closing threads elsewhere due to server volume.
this thread is not about recombination
anonymous – at 08:44
Heh. Depends who you ask. ;-)
The sequence of the cleavage site really does not address recombination or random mutation as a mechanism of the change. There are really two strains circulation in Indonesia, one with RERRRKKR and the other with RESRRRKKR. Each cleavage sequence is associated with a number of other changes.
Chances are RERRRKKR is more lethal and is in the Sumara cluster (while the RESRRRKKR is the the majority of human cases in West Java).
I suspect PB2 E627K is also involved, but there are NO human PB2 sequences that have been released from Indonesia (and these sequences are controled by Hong Kong and the CDC).
DemFromCT—I’ve written my State’s representatives and senators, as well as my governor, but I can’t find an email address for Secretary Leavitt and the other higher-ups at HHS. Do we have theri email addresses somewhere on the FW? Thanks.
Maybe you could call here and get an address:
Address: Ready Campaign U.S. Department of Homeland Security Washington, DC 20528
Phone: 202–282–8000
Email: ready@dhs.gov
Bump
Bump
Bump
before the thread is closed.
This issue is still undecided. Indonesia somehow announced to release the sequences, but nothing is happening.
We still get no comments from experts or officials concerning
resrrkkr. Apparantly they are trying to avoid commenting on this important
issue since 4 months now.
Sign the d*** petition!!!! (sorry! ;-( )
I have two questions, please.
One - maybe best directed to Dr. Niman - does the A90T glycosylation substitution necessarily infer adaptation to the human alpha 2,6 receptor isomer?
Two - maybe best directed to NS1 - is the ability of the virus to dodge interferon related to virulence? I may have misunderstood, but I thought I heard that the bug likely trades virulence for interferon-evasion.
Thanks!
Thanks for bumping this thread, missed it last month. One other small thought is that the S in RESRRKKR (as opposed to RERRRKKR) also has a hydrophilic side chain, like the R’s and K’s.
One question I have is this. I thought that in order to add a glycosylation group to S or T (serine or threonine), there had to be an N (asparagine) two letters away from the S or T.
Example: N-X-T or N-X-S, where X is any other amino acid.
Can someone clarify? If this is a requirement, then there would be no glycosylation site added in this area of the sequence. And if there were a glycosylation site added, wouldn’t it be possible that it could upset the geometry (i.e., it might create mechanical spacing difficulties) of the molecular interactions during the cleavage process? Thanks!
Here’s an article in regards to virulence, which was posted on the news thread but should be on a science thread for discussion. Dr. Peiris and crew in Hong Kong published a report in the Journal of Infectious Diseases, July 2006. The scientists tested the response to 3 influenza viruses: a human H1N1 virus from 1998, an H5N1 virus from 1997, and a 1997 H9N2 virus, on human cells cultures. The viruses had the same rate of replication, yet there was a large difference in cytokine production for H5 and H9 avian virus, compared to the contempory H1N1 human virus. However the reconstituted 1918 H1N1 had the higher cytokine reaction. The difference of the mutations must hold the key for virulence.
“We have demonstrated that human MDMs have differential responses to human influenza virus H1N1/98 and avian viruses H9N2/G1 and H5N1/97, in spite of their similar infectivity and viral replication,” the authors write. “Moreover, stronger chemokine and chemokine-receptor responses to avian influenza viruses were detected in adult MDMs than in neonatal MDMs.”
They add that the higher CCL3 response to H5N1 by adult MDMs, as compared with neonatal MDMs, may be “one of the important factors” in the higher adult mortality rate in Hong Kong’s 1997 outbreak. They note that higher levels of CCL3, along with several other chemokines, have been found in plasma from people who died of H5N1 disease than in people who survived it.
Overall, the authors conclude, “These data suggest that host factors may influence the disease process or outcome.”
“The authors noted that mice infected with the newly reconstituted 1918 H1N1 Spanish flu virus produced high levels of the same immune system signalling chemicals as were seen to be over-produced by the H5N1 and H9N2 viruses. Since these more contemporary avian flu viruses carry a number of the same mutations on their internal genes as the 1918 virus did, they argued, further analysis of the role of these mutations is needed to determine what role they play in the disease process.”
Bumping cause it deserves it. Hope none of those Spanish Flu carrying mice are in a hurricane zone. NJ Prepper-good article to point out to us.
The sequences for HA in Indonesian H5N1 isolates came out today. Most have the H5N1 wild type cleavage site, RERRRKKR, but one, A/duck/Badung-Bali/05/2005(H5N1), has the Qinghai cleavage site GERRRKKR, as well as one of the polymorphisms in the Niger H5N1 sequence.
These polymorphisms are on an Indonesian genetic background.
Recombination is the name of the game.
Although this relates to GERRRKKR and not RESRRRKKR, the appropriate thread has been closed. This cleavage site is much more about recombination and really has nothing to do with RESRRRKKR, which has an unknown source
DQ447199 A/chicken/Egypt/960N3–004/2006 2006 H5N1 DQ406728 A/chicken/Nigeria/641/2006 2006 H5N1 AM231714 A/common pochard/France/06167/2006 2006 H5N1 DQ515984 A/Cygnus olor/Czech Republic/5170/2006 2006 H5N1 DQ435200 A/domestic cat/Iraq/820/2006 2006 H5N1 DQ435201 A/domestic goose/Iraq/812/2006 2006 H5N1 DQ659113 A/duck/Niger/914/2006 2006 H5N1 DQ464377 A/Egypt/2782-NAMRU3/2006 2006 H5N1 DQ435202 A/Iraq/207-NAMRU3/2006 2006 H5N1 DQ458992 A/mallard/Bavaria/1/2006 2006 H5N1 DQ449031 A/mallard/Italy/332/2006 2006 H5N1 DQ440535 A/swan/Iran/754/2006 2006 H5N1 DQ412997 A/swan/Italy/179/06 2006 H5N1 ISDN136919 A/swan/Italy/179/2006 2006 H5N1 AM236074 A/turkey/France/06222/2006 2006 H5N1 AB233319 A/bar-headed goose/Mongolia/1/05 2005 H5N1 DQ095621 A/Bar-headed Goose/Qinghai/12/05 2005 H5N1 DQ095617 A/Bar-headed Goose/Qinghai/5/05 2005 H5N1 DQ095612 A/Bar-headed Goose/Qinghai/59/05 2005 H5N1 DQ095615 A/Bar-headed Goose/Qinghai/60/05 2005 H5N1 DQ095618 A/Bar-headed Goose/Qinghai/61/05 2005 H5N1 DQ095620 A/Bar-headed Goose/Qinghai/62/05 2005 H5N1 DQ095622 A/Bar-headed Goose/Qinghai/65/05 2005 H5N1 DQ095623 A/Bar-headed Goose/Qinghai/67/05 2005 H5N1 DQ095613 A/Bar-headed Goose/Qinghai/68/05 2005 H5N1 DQ095619 A/Bar-headed Goose/Qinghai/75/05 2005 H5N1 DQ100554 A/black-headed goose/Qinghai/1/2005 2005 H5N1 DQ100555 A/black-headed goose/Qinghai/2/2005 2005 H5N1 DQ100556 A/black-headed gull/Qinghai/1/2005 2005 H5N1 DQ095616 A/Brown-headed Gull/Qinghai/3/05 2005 H5N1 DQ340848 A/chicken/Crimea/1/2005 2005 H5N1 DQ449632 A/chicken/Kurgan/05/2005 2005 H5N1 DQ323672 A/chicken/Kurgan/3/2005 2005 H5N1 DQ190859 A/chicken/Novosibirsk/64/05 2005 H5N1 DQ190860 A/chicken/Novosibirsk/65/05 2005 H5N1 DQ190861 A/chicken/Novosibirsk/66/05 2005 H5N1 DQ231242 A/chicken/Suzdalka/Nov-11/05 2005 H5N1 DQ231241 A/chicken/Suzdalka/Nov-12/05 2005 H5N1 DQ279301 A/chicken/Tula/10/2005 2005 H5N1 DQ389158 A/Cygnus olor/Astrakhan/Ast05–2−1/2005 2005 H5N1 DQ434889 A/Cygnus olor/Astrakhan/Ast05–2−10/2005 2005 H5N1 DQ343502 A/Cygnus olor/Astrakhan/Ast05–2−2/2005 2005 H5N1 DQ358746 A/Cygnus olor/Astrakhan/Ast05–2−3/2005 2005 H5N1 DQ363918 A/Cygnus olor/Astrakhan/Ast05–2−4/2005 2005 H5N1 DQ365004 A/Cygnus olor/Astrakhan/Ast05–2−5/2005 2005 H5N1 DQ364996 A/Cygnus olor/Astrakhan/Ast05–2−6/2005 2005 H5N1 DQ363923 A/Cygnus olor/Astrakhan/Ast05–2−7/2005 2005 H5N1 DQ399540 A/Cygnus olor/Astrakhan/Ast05–2−8/2005 2005 H5N1 DQ399547 A/Cygnus olor/Astrakhan/Ast05–2−9/2005 2005 H5N1 DQ449640 A/duck/Kurgan/08/2005 2005 H5N1 DQ190858 A/duck/Novosibirsk/56/2005 2005 H5N1 DQ230522 A/duck/Novosibirsk/56/2005 2005 H5N1 DQ320922 A/Environment/Qinghai/31/2005 2005 H5N1 DQ100557 A/great black-headed gull/Qinghai/1/2005 2005 H5N1 DQ095614 A/Great Black-headed Gull/Qinghai/2/05 2005 H5N1 DQ320919 A/migratory duck/Jiangxi/2136/2005 2005 H5N1 DQ320920 A/migratory duck/Jiangxi/2295/2005 2005 H5N1 DQ320921 A/migratory duck/Jiangxi/2300/2005 2005 H5N1 DQ453141 A/mute swan/Croatia/1/2005 2005 H5N1 DQ320137 A/swan/Astrakhan/1/2005 2005 H5N1 DQ231240 A/turkey/Suzdalka/Nov-01/05 2005 H5N1 DQ407519 A/turkey/Turkey/1/2005 2005 H5N1 AB233320 A/whooper swan/Mongolia/3/05 2005 H5N1 AB233321 A/whooper swan/Mongolia/4/05 2005 H5N1 AB233322 A/whooper swan/Mongolia/6/05 2005 H5N1 ISDN48972 A/Chicken/Hu bei/14/2004 2004 H5N1 AY830774 A/chicken/Macheng/2004 2004 H5N1
The Sarge – at 09:45
I don’t know much about interferon-evasion? The virus doesn’t really move away from the interferon. It reduces the interferon response to the host cell via multiple pathways. Less interferon is produced and, of that lower response, less penetrates the cell membrane to limit viral replication.
Virulence is then, in fact, increased because replication continues primarily unchecked until later response mechanisms come into play. The virus gets a substantial headstart on the immune system.
In viral genetics (non-H5N1), many cases of correlated up-modulations of one feature with down-modulations of another. Causality is harder to establish.
In the H5N1 world with particular emphasis on the NS1 segment, the so-called tradeoff you mentioned is not so evident to me.
beehiver – at 10:02
You may find a moderate different in the Arginine and Lysine which are very hydrophillic and the Serine which is somewhat ambivalent (uncharged).
Most proteases cleave after basic amino acids (R and K). Exchnaging and S for an R probably limits infection of some tissue types (that have proteases that cleave after the second R in RERRRKKR.
Copied from the Limericki thread, because it’s relevant:
Scaredy Cat – at 13:06 There once was a sequence named RERRRKER. (Wait, maybe I’m thinking of GERRRKER.) What’s confusing to me Seems clear as can be To NS1, niman and Racter.
any idea, why the S could be more suitable to humans (or cats? or pigs?), while the R is in chickens ? It also could be just geographic-specific, but looks more likely to me that it is species-specific.
Probably not correlated to species.
NS1 -
Sorry, imprecise language. I should have said evading the effects of interferon. But, you answered my question. Thanks!
Oooh, thanks Dem. I need that link. I love learning more on the genetics side of things. And since I don’t know more, how far along are the mutations currently observed in H5N1 compared to the mutations that have been deemed worth watching for due to similarity to 1918 H1N1? Aside from E627K and S227N, which have already been discussed? I just remember reading Webster’s words of warning.
anonymous. R isn’t species specific. The 1996 goose was RERRRKKR and that cleavage site is dominant and has been found in many species in Asia.
it interacts with other mutations. Maybe in the Indonesian (Java) strain it is species-specific ?
anonymous, There are lots of polybasic cleavage sites. In most countries, the sequnece crosses species barriers rather easily. Almost all Qinghai sequences have the GERRRKKR cleavage site. That is present in the human isolates infceted with the Qinghai strain (in Turkey, Iraq, Egypt, Azerbaijan, and Djibouty (and of course teh same cleavage site is in Qinghai isoaltes from well over two dozen bird species as well as the cat (and I presume, dog, stone martin, and any other H5N1 infected host in Europe, the MIddle East, and Africa).
In Vietnam and Thaland, the human isolates had the common RERRRKKR sequence initially, and then it changed to RERRKKR (list an R). The Fujian strain has lost a K, so it is RERRRKR and it is inbirds and all reported recent human cases in China.
The only place that the HA cleavage sites doesn’t match the bird sequences is Indonesia, where RESRRKKR is only in humans and a cat as shown in the phylogenetic tree.
yes, and the question is, whether they just failed to find the avian sequences with RESRRKKR or whether RESRRKKR survives better in humans while RERRRKKR survives better in birds. Swine in Java seem to have RERRRKKR too. This could be tested in a lab, maybe. Indect some mice,chicken,ferrets,cats with RESRRKKR and/or RERRRKKR and see which virus can be isolated after death. Looks important enough to me. Maybe it is being done, since we hear nothing from the Peter Roeder team in Indonesia.
No, the differences extend beyond the cleavage site, as shown in the phylogenetic tree linked above (all of the RESRRKKR isolates are in the lowest branch of the tree).
Thanks for posting here again, Dr. Niman.
yes, I see. These must be the 21 viruses at the bottom,
which are at least 10–20 nucleotides apart from the next chicken
IDN/176H/95
CK/KulonPnoonBEVET8VDM (or such)
seem closest
NS1 at 06:35 asked “A mutation is defined as a random event. Why would you expect a random event to be repeated at least 11 times?”
Depends on how likely a mutation is and how many chances it has to occur. Those mutations which are fit may be propagated to further generations, those which are not fit won’t.
You may not expect a coin to come up heads 10 times in a row, right ? Yet in sequences of millions of tosses, such an event becomes likely. It becomes even more likely under positive selection: Take 11264 pennies, toss them all at once; remove all that come up tails. Repeat 9 more times. The ones you have left have come up heads 10 times in a row. How many would you expect to end up with ? 11.
NS1 at 07:27 said: “A mutation by definition is random. Random events do not occur 1 of 10 times except on the 7th planet.”
Unless the probability of the event is 10%, in which case in a large sample you can expect a rate close to 1 in 10. The probability of a tossed coin landing heads up is 50%. The random event of “heads” can be expected to occur once of every two tosses.
has it been observed in other cases, that the mutation rate of the same virus changes dramatically depending only on some host.factor (which?) ?
oops, wrong thread. aAkova quotes from old posts.
a’Akova – at 03:00
A coin toss is binary and the rules are known, so it cannot be compared to a polymorphism.
NS1, did you have a look at the phylo-tree ?
Looks like an unknown intermediate host ?
I wonder, how the distant the Karo-cluter viruses are from the other human viruses in Indonesia. We can’t see it from the tree. Do we need two different intermediate host-species, one for Java, one for Sumatra ?
The tree shows that the human cases have mnore in common than just RESRRKKR in common. They form their own btanch, which requires that they have several changes in common.
yes, and that they are different from the chicken.
And maybe even two branches, one for Java, one for Sumatra.
However the RESRRKKR was somehow established and fixed - we see too few
cases without RESRRKKR to assume that this ist just random or
coincidental. It is probably advantageous in humans or in some
intermediate species.
Any speculation about the reason and about intermediate hosts ?
Feel free to speculate, we won’t nail you on that…
Could someone please check the fruit bats? I understand they taste like chicken. Indonesia has like 65 species, the most in the world. And they come out at night, unlike the sampling teams.
anonymous, The surveillence in Indonesia remains exceedingly poor. At this time the most likely mammalian reserve is homo sapien.
Became provokated :) Just wanted to share a few links with you..:
http://messybeast.com/eat-cats.htm
http://www.capital.net/com/phuston/cateating.html
http://www.saveacat.org/acr_articles/asiancats.htm
http://asiarecipe.com/chidine.html
“An estimate by the Yangcheng Evening News suggests that a cat stall in the game-meat market can easily sell 300–400 kilograms of cat meat daily in winter. There are about 80 stalls selling cats in the three [game meat] markets. This adds up to 10,000 cats a day.”
Quote: Originally Posted by niman Two of the frecently submitted H5N1 chicken sequences from Indonesia have the novel cleavage site, RESRRKKR.
However, they were both isolated in 2005 and represent a small subset of 2005/2006 poultry isolates
ISDN208031 A/Chicken/Murao Jambi/BBPV-II/2005 2005 H5N1 ISDN208035 A/Chicken/Pakun Baru/BPPV-II/2005 2005 H5N1
Murao Jambi appears to be in Sumatra (south)
http://encarta.msn.com/encnet/featur…pClickCheck=on
Pakun Baru also appears to be on Sumatra, but in central Sumatra not far from Singapore
Last edited by niman : Today at 07:16 AM.
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anonymous. I know you have brought this thread up because you think it is important. You could only do that if you study flu wiki. Rather than just being one of the spammers, why don’t you join us…Thanks.
OK, since the domain this guy’s pushing didn’t make it through the filter I’ll let that one stand so Tom’s post makes sense.