Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

More 3 legged dog stories.

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Commentary

http://www.recombinomics.com/News/06020801/H5N1_Shift_Failures.html

[tropical]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Source: http://canadianpress.google.com/arti...HKailnUqgYJz4g

Study shows hybrids of bird flu and human flu viruses fit well, could occur
...
TORONTO ? An experiment mating H5N1 avian flu viruses and a strain of human flu in a laboratory produced a surprising number of hybrid viruses that were biologically fit, a new study reveals.
...
The work suggests that under the right circumstances - and no one is clear what all of those are - the two types of flu viruses could swap genes in a way that might allow the H5N1 virus to acquire the capacity to trigger a pandemic. That process is called reassortment.
...
Nor can anyone say why, if the viruses swapped genes so readily in the laboratory, that hasn't seemed to have happened in the parts of the world where H5N1 has been circulating for years.
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This work, done at the CDC, was conducted to study the reassortment potential of H5N1 and H3N2 viruses. H3N2 is one of two human influenza A viruses that cause disease during flu season.
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The researchers created 63 viruses representing the various potential combinations of human and avian internal genes, using an H5N1 virus that circulated in Thailand in 2004 and an H3N2 virus recovered in Wyoming in 2003.
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By studying the combinations that succeeded and failed, the scientists were able to start to see patterns of which gene combinations are critical for an H5N1 virus to thrive.
When the most viable viruses were tested in mice, none was as nasty as H5N1. "That's the good news," Donis says, alluding to the fact that if reassortment turns H5N1 into a pandemic strain, the resulting virus could be less virulent than the current version.
...
Both the viruses from the 1957 and 1968 pandemics carried an avian PB1 gene. The authors suggest that picking up an avian PB1 gene may be a critical step in a potential pandemic virus arising through reassortment.
But just because the viruses mated successfully in a laboratory doesn't mean those viruses could go on to trigger a pandemic. In order to have that potential, a virus would have to be able to transmit from person to person - a skill that has so far eluded H5N1.
"The bottom line is it comes back down to transmission really being the key," Webby says. "But to say that we understand what are the factors involved in transmission is certainly an overstatement."
Earlier work at the CDC on some H5N1-H3N2 reassortant viruses showed they failed to transmit from infected to uninfected ferrets, an animal often used in flu research.

All this reasearch based on suceeds and fails experimenting, apart of the numerous animal deaths, looking from the upper text (the marked statements) nobody would be able to prove what strain would go pandemic, nor if it would be less virulent realy.

The main sure thing is there are in the freezers 63 more lethal avian/human (previously non-existant) viruses - now for real.

[gsgs]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

it would be useful to test these viruses for transmissiability in some typical
human community.
However we can't do that in most countries for ethical reasons.

So we need some animals, which can simulate human contacts
and have similarsusceptability to the viruses.

Or we make it less virulent while keeping the transmissiability

Or we simulate it on computer with just some laboratory transmission data

But then, we don't even know how much normal flu transmits
by droplets/airosoles/contact.
I don't understand, why it's so difficult to figure this out.
Maybe it's because of the secrecy, because researchers don't
collaborate well, because doctors don't examine and collect data
about from where patients got the virus.

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

All this reasearch based on suceeds and fails experimenting, apart of the numerous animal deaths, looking from the upper text (the marked statements) nobody would be able to prove what strain would go pandemic, nor if it would be less virulent realy.

The main sure thing is there are in the freezers 63 more lethal avian/human (previously non-existant) viruses - now for real.

Yes, and they are ALL less lethal than H5N1, which is far more widespread than just freezers.

[tropical]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Yes, and they are ALL less lethal than H5N1, which is far more widespread than just freezers.

I agree that H5N1 are more widespread, dr. Niman.

You would certainly know better than me.
What I want to said is that seems from the cited text, that now we have in the freezer created avian-human hybrid viruses biologicaly fit ("a surprising number of hybrid viruses that were biologically fit"), at the same time where in nature we have not an biologicaly fit human-avian version capable of transmiting itself?
Or it is?

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

I agree that H5N1 are more widespread, dr. Niman.

You would certainly know better than me.
What I want to said is that seems from the cited text, that now we have in the freezer created avian-human hybrid viruses biologicaly fit ("a surprising number of hybrid viruses that were biologically fit"), at the same time where in nature we have not an biologicaly fit human-avian version capable of transmiting itself?
Or it is?

Biologically fit only means that they can grow. It doesn't mean that they can compete (and the failure to find such reassortants in nature puts them well into the 3 legged dog category).

[AlaskaDenise]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Commentary

http://www.recombinomics.com/News/06..._Failures.html

Commentary

More Human Avian Influenza Genetic Reassortment Failures
Recombinomics Commentary 15:20
June 2, 2008

And while none of the offspring viruses was as virulent as the original H5N1, about one in five were lethal to mice at low doses, showing they retained at least a portion of the power of their dangerous parent.

The work suggests that under the right circumstances - and no one is clear what all of those are - the two types of flu viruses could swap genes in a way that might allow the H5N1 virus to acquire the capacity to trigger a pandemic. That process is called reassortment.

"This study is just showing exactly that: There is a risk this virus can successfully reassort with a human virus," said Richard Webby, director of the World Health Organization's collaborating centre for influenza research at St. Jude Hospital in Memphis, Tenn.

"The problem is we don't know at this stage whether there's a benefit to these H5N1 viruses in doing that."

Nor can anyone say why, if the viruses swapped genes so readily in the laboratory, that hasn't seemed to have happened in the parts of the world where H5N1 has been circulating for years.

The above comments on the recent paper in PLOS demonstrates the inherent problem with human / avian reassortants involving H5N1. H5N1 has already evolved into an effective killing machine that not only can kill a wide variety of avian species, but can also kill mammals. This has been demonstrated time and again with humans, as well as mammals that eat H5N1 infected birds. Moreover, H5N1 has evolved into multiple sub-clades capable of producing confirmed fatal infections in humans. Clade 1 has produced fatal human infections in southeast Asia (Vietnam, Thailand, Cambodia). Clade 2 has been divided into three major subclades. Clade 2.1 has produced confirmed fatal infections in Indonesia. Clade 2.2 (Qinghai strain) has produced confirmed fatal infections in Turkey, Iraq, Azerbaijan, Egypt, Nigeria, Pakistan. Clade 2.3 (Fujian strain) has produced fatal infections in China, Vietnam, Laos, Cambodia. All of these fatalities have been in the past few years, demonstrating that relatively minor changes in individual genes can extend the lethality for humans to a variety of H5N1 sub-clades currently in circulation.

The property required to move H5N1 into the pandemic category is not grow in mammals or virulence in mammals, it is efficient transmission between mammals. Virtually all of the clusters in the above countries include human to human transmission between family members or close contacts. However, such transmission chains have generally been limited to a few transmission cycles.

For clade 2.2, most of the clusters have been associated with receptor binding domain changes which enhance affinity for human receptors, and in several cases decrease affinity for avian receptors. However, these changes involve alterations at one or two positions. They do not involve reassortment, which swaps one or more entire genes.

Thus, the examples in the recent PLOS paper are primarily the “B list” of reassortants that are viable, but are usually not lethal in mammals. The small list of those that retain lethality have not been shown to increase transmission. Those candidates, which represent the “A list”, were published earlier in a PNAS paper. However, the “A list” also failed to match the growth or transmission efficiencies of H5N1 with eight avian gene segments, representing naturally evolving H5N1.

The failures of reassortants have led some to question whether H5N1 will develop into a pandemic strain. However, it is the successes in increased transmission efficiencies in H5N1 with receptor binding domain changes in human clusters that suggests a pandemic is only one or two nucleotide changes away.

Ironically, it is an H7N2 human / avian reassortant that has produced enhanced transmission in a ferret model, but the removal of the H7N2 sequences from Genbank shortly after the sequences were made public has created confusion on the true genetic composition of A/New York/107/2003, which was isolated from a case infected in 2002 in New York. The deposited sequences have 3 avian genes (HA, NP, NA) and 4 human genes (PB1, PA, MP, NS). The 8th gene sequence, PB2, wasn’t made public. The enhanced receptor domain binding and ferret to ferret transmission was highlighted in a recent PNAS paper. Moreover, if the submiited gene sequences are correct and the patient tested negative for H3N2, then the infection was likely transmitted human to human.

Although the published results have generated a great deal of media attention, the removal of the underlying sequences has not, and the authors of the study have not publicly commented on the sequences, which are not currently marker with a red banner stating that This record was removed at the submitter's request because the source organism cannot be confirmed.

Ironically, the CDC in Atlanta was involved in both studies, as well as a recent paper in Science on the global spread of H3N2. That paper included sequences, including one submitted by the CDC, which confirmed H3N2 HA recombination in patients in Korea in 2002. Both reassortment and recombination involve swapping of genetic information in hosts co-infected with two or more influenza viruses. While the ressortment swaps whole gene segments, recombination involves swapping portions of genes, which may lead to exchanges of single nucleotide polymorphisms, which is the type of change than can alter binding affinities for human or avian receptors.

The ressortment, or swapping of whole genes, is called genetic shift, while the changes in single nucleotide polymorphisms is called drift. One of the basic tenets of influenza genetics holds that the drift is due almost exclusively to de novo copy errors which happen during viral replication. However, the number and patterns of changes support acquisition via recombination.

Regardless of mechanism, sequence analysis demonstrates that stable small changes are far more frequent than stable reassortants, which is why an H5N1 pandemic is much more likely to involve a change in the receptor binding domain that increases affinity for human receptors, than a swapping of whole avian genes fro human genes.


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[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

I agree that H5N1 are more widespread, dr. Niman.

You would certainly know better than me.
What I want to said is that seems from the cited text, that now we have in the freezer created avian-human hybrid viruses biologicaly fit ("a surprising number of hybrid viruses that were biologically fit"), at the same time where in nature we have not an biologicaly fit human-avian version capable of transmiting itself?
Or it is?

A human / avian combo in H5N1 has never been reported in the field. There is no evidence to support such a combuination that would be more fit than the current H5N1 with 8 avian genes. Replacing avian genes with human genes weakens the virus. Some don't grow, many grow poorly, and a small number cause significant disease in mice.

These lab experiments, which have been ongoing for a decade, have never created a combination that matched the avian H5N1's abilities to produce disease and transmit in mammals.

The experiments were designed to create a virus that was MORE TRANSMISSIBLE. All such experiments to date have been dismal failures, although many different H5N1's have been used with many different human flu gene combinations.

[mixin]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Niman:

The experiments were designed to create a virus that was MORE TRANSMISSIBLE. All such experiments to date have been dismal failures, although many different H5N1's have been used with many different human flu gene combinations.

Are you positively sure they would announce a success?

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Niman:

Are you positively sure they would announce a success?

Please, the hundreds of millions in funding is based on a reassortment success.

They would publish in a heart beat.

[gsgs]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

they may have signed secrecy agreements, so if the funding
institute doesn't want to publish then the researchers may not
either.
Think military funding

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

they may have signed secrecy agreements, so if the funding
institute doesn't want to publish then the researchers may not
either.
Think military funding

Nonsense.

[HenryN]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

they may have signed secrecy agreements, so if the funding
institute doesn't want to publish then the researchers may not
either.
Think military funding

I think you should start a separate internet / conspiracy thread, where your comments would be more relevant.

[mixin]

Re: Genetic Compatibility and Virulence of Reassortants of H5N1 and H3N2

Please, the hundreds of millions in funding is based on a reassortment success.

They would publish in a heart beat.

Yes, if that is the reason for funding.

We don't even know the number of labs in the U.S., so I'm not convinced anyone can know exactly what is being done in all of them.

I'm not sure it's a *theory* that there are military contracts that will be kept secret.