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looks to me as if D225G is created independently in the hosts
and is not introduced by mixed viruses.
So it appears late in the disease and is not transmitted
and appears on different genetical backgrounds
Forgive an ignorant question, but am I understanding correctly that D225G is generated during the evolutionary process within a single host while they are sick and not circulating separately in a mutated virus?
If this is true, then wouldn't the severe cases be observed as a fairly consistent percentage of all cases and result in similar death rates all over the world? It appears that we have regions of higher death rates with no obvious common causes associated with socio-economic conditions, poor health care, etc.
"I know God will not give me anything I can't handle. I just wish that He didn't trust me so much." - Mother Teresa of Calcutta
looks to me as if D225G is created independently in the hosts
and is not introduced by mixed viruses.
So it appears late in the disease and is not transmitted
and appears on different genetical backgrounds
As bizarre as that sounds, it might be the case. At least that story would be epidemiologically consistent with what we have seen. And perhaps the mutation is more likely to occur in a patient with a high viral load (more viruses means more chances for mutation), and perhaps poor health care in some areas and pre-existing conditions would make high viral loads more likely.
The epidemiology of the past seven months is utterly inconsistent with two separate viruses co-circulating, and the existence of the mutation in April rules out a recent change. So I remain stumped.
As bizarre as that sounds, it might be the case. At least that story would be epidemiologically consistent with what we have seen. And perhaps the mutation is more likely to occur in a patient with a high viral load (more viruses means more chances for mutation), and perhaps poor health care in some areas and pre-existing conditions would make high viral loads more likely.
The epidemiology of the past seven months is utterly inconsistent with two separate viruses co-circulating, and the existence of the mutation in April rules out a recent change. So I remain stumped.
Why would a higher viral load = more mutations? It might lead to more recombination events (possibly tho I am not convinced of that either, its not a given in all cases) but, as a rule, cis-genomic events like spontaneous mutations are not driven by viral load.
We hardly know anything about this disease.
We pretend to understand it, we have some primers against a dominant strain. We have no clue about the prevailing heterogeneity of strains in any particular carrier background.
Its important to not extrapolate too far into hypotheses that are unlikely based on an incomplete understanding of the disease in the first place.
Not to mention the fact that we, outside of Mill Hill and related labs, have only a very small amount of the data that is being generated during the pandemic plus the "fog of war" that will conceal much for some time (for ever?)
Re: 225G Preliminary Worldwide Tracking & Evaluation
A higher viral load would mean more viruses replicating. If there is a small (but fixed) change that each replication would produce a mutation, then the more viruses in a patient (the higher the viral load), the higher the risk of mutation. That seems to make sense to me.
But you're right, I don't understand where this mutation is coming from, and most of the theories proposed so far are incompatible with the data.
A higher viral load would mean more viruses replicating. If there is a small (but fixed) change that each replication would produce a mutation, then the more viruses in a patient (the higher the viral load), the higher the risk of mutation. That seems to make sense to me.
But you're right, I don't understand where this mutation is coming from, and most of the theories proposed so far are incompatible with the data.
If you ascribe to the passage effect (suboptimal replication machinery along a specific pathway (?)) as a global mechanism for the statistically improbably simultaneous appearance of the same mutation in widespread locations. I dont really buy into some "preprogrammed" pathway for mutation generation.
If there is data for that, it would be interesting to see and am open to see it.
WHO and others have remarked often that pandemic H1N1 is quite stable.
"Stable" can be a tricky term. To WHO etc stability might mean that the dominant disease causing strain remains sufficiently identical to the reference seed strains (against which the vaccines were developed) such that the vax remains effective (for now, but the world is a BIG place).
That meaning of stable can mean nothing in the face of the degeneracy of triple codons, replication efficiency, and strain heterogeneity in this pandemic.
Just because we can produce vaccines (only possible because of the "black box" of nature) doesnt mean we have the science or computing power to sufficiently grok the complexity of this simple 8 gene "life form" as it interacts with the billions of immune systems on this planet.
A higher viral load would mean more viruses replicating. If there is a small (but fixed) change that each replication would produce a mutation, then the more viruses in a patient (the higher the viral load), the higher the risk of mutation. That seems to make sense to me.
A higher viral load ? doesn?t that also mean a sicker patient?
The mutated virus has also been found in several mild cases?.how does this goes into the ?host mutation? theory?
Re: 225G Preliminary Worldwide Tracking & Evaluation
most important for 225G then is time.
When that mutation happens, there are probaly already
gillions of other viruses around which compete for cell-entry.
Now the mutated virus may be able to infect cells which the others couldn't.
But then it must still replicate and get a considerable load
as compared with the nonmutated viruses.
And one replication cycle takes 6-10 hours.
So 225G would not be detected when people first
have symptoms and are tested.
Is this the case ?
Were all the 225Gs detected late in the disease ?
Re: 225G Preliminary Worldwide Tracking & Evaluation
the mutation, when it occurs, needn't make people equally sick everywhere.
It could depend on other mutations,
on host genetics,nutrition etc. (as usual)
but other mutations could pave the way to make it more
prevalent and spread in the saliva or breath
then we get a 2nd strain competing with the current American one.
most important for 225G then is time.
When that mutation happens, there are probaly already
gillions of other viruses around which compete for cell-entry.
Now the mutated virus may be able to infect cells which the others couldn't.
But then it must still replicate and get a considerable load
as compared with the nonmutated viruses.
And one replication cycle takes 6-10 hours.
So 225G would not be detected when people first
have symptoms and are tested.
Is this the case ?
Were all the 225Gs detected late in the disease ?
Is it a matter of time or location? It sounds like the two theories are that 225G is a common mutation that occurs within a single host and then drives the course of the disease due to its ability to infect the deep lung tissue. The other is that there is a variant circulating with 225G and that it is causing the more severe illnesses. In either case, it seems that it would difficult to isolate the variant without getting a sample of lung tissue or sputum from deep in the lungs.
"I know God will not give me anything I can't handle. I just wish that He didn't trust me so much." - Mother Teresa of Calcutta
From some recent sci. releases (some recent FT thread),
it could be a matter of hosts.
Bodies which have naturaly much more deep lung receptors,
receive in the same time a mcuh more quantity of viruses in deep lungs than bodies with low quantities of lung receptors in deep lung.
Because of that, they accumulate huge quantities of virus in few days,
and by cytokine reaction gone to a lung toxic distress reaction.
The others have a mild or moderate reaction only, for the same bug.
The above could explain why the same more lung receptor prone virus was isolated from both, mild and deadly case.
Re: 225G Preliminary Worldwide Tracking & Evaluation
There could be some sort of host genetic component to this mutation event such as a human transcriptase that in a certain form "frequently" (I use that term relatively) makes the same mistake in transcribing that site. This could be the reason behind higher death rate in native population. Once the mutated virus is made it still must infect the deep lung cells or it will only present as a mild case. I was merely suggesting this as a possibility and have no data to back it up.
are Ukrainian bodies different from those in USA or other Europe ?
why so much in Lviv and F.
Obviously every body is enaugh diferent if we include all the stories about:
radionuclides/arsenic/vitD3/denutrition/late hospitalization/various areas enviro-intoxication/...
The increased infections rates in short time could be from some viral changes.
The Ukraine cfr was at FT posts many times depicted as "similar to elsewhere".
Other areas more afected could have diferent populations qualities for the virus.
The main question was if the actual/from the begining elsewhere also/ mutation is a diferent virus variant which when infect cause mainly deadly cases, or it is the same variant (or multiple similar variant),
which (or all of them) made many mild cases for now (no matter the various actual mutations or increased infections in time),
but in some subjects having much more deep lung receptors, are capable to invade the lungs in big viral numbers in short time (hours/few days) and drive to cytokine toxic distress.
___
"For the two 1918 HA variants, the South Carolina (SC) HA (with Asp190, Asp225) bound exclusively alpha2-6 receptors, while the New York (NY) variant, which differed only by one residue (Gly225), had mixed alpha2-6/alpha2-3 specificity, especially for sulfated oligosaccharides.
The above description is from a paper analyzing receptor binding domain differences in sequences from the 1918 pandemic. The New York variant had D225G, the same change found in lung tissues from fatal swine H1N1 sequences in Brazil, Ukraine, and Norway."
If the NY variant is not the California one, than in Ukraine were both, if the NY/Brazil/Ukraine/Norway is to blame for the deadly cases.
From the above, at the field on Ukraine were at least 2 variants of pandemic viruses, not one (California) only,
and than we have an additional problem,
because in that case there is an "old" deadly strain now spreading worldwide in more areas.
Stil, the increased in time infections in Ukraine, plus the possibility of stohastic hosts pandemic virus preference, and worldwide reports of Tamiflu resistance, makes more worst the potential further spreading picture.
This health estabs tecnic of makes retrology 6 months after, without any containment (apart Ukraine, and few areas), does not make any help for pandemic disease containment.
Remains the help of esigue vaccines quantities, with personal assumption of vacc. risks, which could vanish if the strain will change enaugh.
Mutation in the Haemagglutinin gene of pandemic Influenza A(H1N1)v reported from Norway
The Norwegian Institute of Public Health reported on 20 November 2009 the detection of a mutation in the viruses affecting three cases of severe pandemic Influenza A(H1N1)v infection . Overall approximately 70 influenza viruses from ill patients have been sequenced in Norway, including six from patients who died.
The three viruses with this mutation were isolated from the first two fatal cases of pandemic influenza in Norway and one patient with severe respiratory disease. The two fatal cases , who were not epidemiologically linked, died in July and August, 2009.
Based on the currently available information it appears that the mutated virus is not circulating in the Norwegian population, but may the result of a spontaneous change occurring in severely ill patients [1].
In a note responding to the report from Norway WHO reported that worldwide, a similar mutation has been was detected in viruses from several other countries, with the earliest detection reported in April.
In addition to Norway, the mutation has been observed in Brazil, China, Japan, Mexico, Ukraine and the USA.[2]
The amino acid change in the haemagglutinin HA1 gene at position 222 (225 in influenza H3 numbering) from aspartic acid (D) to glycine (G) observed, may influence receptor binding specificity and therefore has the potential to affect the pathogenicity of the virus. This might allow the mutated virus to infect tissues deeper in the respiratory tract, although the receptor binding preferences have not been determined yet.
Currently, there is no evidence about the consequences of this mutation on the biological properties of the virus. In addition, if the receptor preference of the mutated virus corresponds to the deeper airways, this most likely will tend to reduce the likelihood for easy human-to-human spread.
A likely explanation of this finding is that it is an adaptive mutation of the virus. At this moment there is no indication of change in the virulence of the circulating pandemic Influenza A(H1N1)v virus.
The virus with this mutation remains sensitive to oseltamivir and zanamivir.
Studies show that the currently available vaccines confer protection.
Continued close virological monitoring in particular of severe cases, is needed to elucidate any potential relationship between the mutation and the clinical outcome of infection.
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