Posts Tagged ‘D225G’

Swine Flu Update

By Ilene

Previous series of swine flu updates by me here.

Transmission of Fatal H1N1 D225G/N Accelerates Concerns

Ukraine takes measures to combat swine flu, closes all school - Kiev

Courtesy of Dr. Henry Niman, Recombinomics Commentary

Recently released H1N1 HA sequences have significantly accelerated pandemic concerns.  These sequences have either D225G, D225N, or both and produce a case fatality rate at or near 100% in many countries…. 

By the 100% fatality rate, Dr. Niman means that they are finding these changes in the tested fatal cases in some countries.  Keep in mind, these are small numbers of cases.  It does not mean that all cases with these changes prove fatal.  It might be more clear to say a large portion of the fatal cases show these changes in the infecting viruses.

[the] transmission and expansion of these fatal sequences in eastern Europe, including Russia have increased concerns, as has the "low reactor" status as determined by Mill Hill for a tested Ukraine sequence.

Some of the earliest sequences with D225G were in the United States last spring and were generally mild.  However, initial cases in the US were generally mild, which may have reflected low  viral loads infecting a naïve population…

"Low reactors" status means that the virus is not triggering the immune response expected due to changes in the structure of certain viral proteins (here, the influenza hemagglutinin proteins).  Immune responses target specific proteins and the target proteins’ structure is critical to the immune response.  Not all changes in a protein will greatly reduce its immunogenicity (ability to stimulate the immune response) but certain changes will.  The change from the wild-type (common) HA protein to the HA protein with the D225G marker appears to have this adverse effect--i.e., the altered viruses will not provoke the stronger immune response generated in response to the wild-type virus and/or the swine flu vaccine.   

These observations are cause for concern, not alarm.  The changes in the H1N1 virus are natural and predictable; Dr. Niman predicted these changes would occur.  

There already was interest in position 225 for a number of reasons.  D225N  was in seasonal H3N2 and linked to the fixing [establishment of widespread] of adamantine resistance (S31N), while D225G was in 1918 and 1919 samples and linked to a change in receptor binding domain specificities which would target subsets of cells in the lung.  In addition, the polymorphism [genetic change] was jumping from one genetic background to


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Flu News

Here’s the latest by Dr. Henry Niman. I’ve made a few helpful comments in red. – Ilene

D225E and D225N H1N1 RBD Changes in Turkey

Courtesy of Henry Niman, PhD

Swine flu virus, showing the structure of the virion: the outer proteins hemagglutinin and

Recombinomics Commentary
January 5, 2010

The Refik Saydam National Public Health Agency has released 29 HA [hemagglutinin] sequences from Ankara, Turkey. Several were partial sequences, but 26 covered the receptor binding domain and 8 had D225E,… while one had D225N,… 

My comment:  D225 is the most common or wild-type receptor binding protein - the hemagglutinin (HA) protein – which enables the virus to bind to tissues in the respiratory tract of infected people. 

A change in the amino acid in position 225 of the receptor binding domain (RBD) is symbolized by using the letter representing the new amino acid, e.g. "G" for glycine in "D225G." The marker D225G signifies that a glycine (G) is present in the 225 position, replacing the amino acid usually in this position, aspartic acid, or D (hence the wild-type marker is "D225"). Glutamic acid, E, and asparagine, N, are two other amino acids that have been found in this position in non-wild-type swine flu viruses.

The change in the receptor binding protein from D to G alters the protein’s preference for binding to human tissues. Viruses with the D225G marker bind in the lung tissue, rather than binding in the upper respiratory tract (nasal area and throat), the more typical target. This appears to result in more severe disesase which may trigger a "cytokine storm" reaction in the lungs.  Whether substitution with "E" or "N" causes similar changes is not known. Theoretically, if the immune response is generated against the wild-type protein D225, viruses with D225G, D225E or D225N markers might avoid the immune system’s response. 

[Back to Dr. Niman] The outcomes of these patients were not given but media reports have described a rapid in increase in H1N1 fatalities in Turkey.  A large number of HA sequences with D225E has been published from Spain, and recently released GISAID sequences from Sweden and the UK also have D225E, including three fatal cases from Sweden. The prior reports of D225G and D225N associations with fatal cases has raised concerns that changes at position 225 could alter tissue tropism or aid in immune escape, leading to more severe and fatal cases.

In…
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H1N1 Update

H1N1 Update:  Watching and Waiting  

by Ilene with guest expert Dr. Henry Niman at Recombinomics

EM of swine influenza (H1N1) virus particles (virions), determined to be the cause of the

Watching and Waiting

Although the numbers of new cases of swine flu have been declining in many regions, including the United States, it is too early to know whether or not there will be subsequent waves of disease.

"Based on my experience with new diseases and the lessons learned from past pandemics, I think we should remain cautious and observe the evolution of the pandemic over the next six to 12 months before declaring victory," World Health Organization Director General Margaret Chan tells Swiss newspaper Le Temps. (World Health Official Says Swine Flu Still a Threat)

Although the WHO is taking a cautious approach, changes in the virus’s genome that increase its virulence and resistance to Tamiflu are becoming more common.  Dr. Henry Niman, expert in flu virus evolution, believes another wave of flu illnesses will occur in early 2010.  In addition, he believes resistance to Tamiflu will become "fixed," similarly to how this genetic change evolved in the seasonal H1N1 virus.  (See Flu Update: Tamiflu resistance and Ukraine update, and Efficacy of Roche’s Flu Drug Tamiflu In Doubt, by David Phillips.)

WHO: H1N1 swine flu pandemic will stick around for another year

The World Health Organization warned government health authorities to remain vigilant on the H1N1 swine flu pandemic, saying the virus could mutate before vaccines can help it dissipate.

The World Health Organization is confident that the H1N1 swine flu pandemic will be under control in a year’s time – however, WHO officials warned global governments to remain vigilant for any mutations in the troublesome bug.

Dr. Niman believes this wave will be more severe than the previous two--but not due to random mutations. Rather, this will result from the process of recombination. Due to recombination, increasingly greater transmission of aggressive variants (D225G, D225E and D225N) and Tamiflu-resistant viruses will occur.

Ukraine

I’ve reprinted two recent articles at Recombinomics, with my comments in blue.

The WHO Surprise on D225G / D225N H1N1 Fatalities, Recombinomics Commentary

After considering the current available virological, epidemiological and clinical findings and following discussions on an earlier draft with WHO and its European-based Collaborating Centre ECDC has come to a preliminary formulation namely that the G222D/N


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Swine Flu Virus: Changes and Consequences

Swine Flu Virus: Changes and Consequences 

By Ilene with guest expert Dr. Henry Niman

Russia and Ukraine take measures to combat swine flu

Background

Dr. Henry Niman heads the research company Recombinomics Inc. Recombinomics has a small group of researchers who analyze the sequence data from viral samples isolated from patients diagnosed with swine flu. Its website is a terrific place to find the newest information available. 

Dr. Niman has kindly been answering my questions regarding the H1N1 virus, its evolution, and the implications regarding the spread of disease. Because the terminology may be unfamiliar, a brief introduction may be helpful towards better understanding both the H1N1 virus and the swine flu disease.

Recombination

Flu viruses, including the H1N1 varieties, are known for quickly changing genetically. Recombination is the driver of rapid molecular evolution, a process whereby small bits of genetic information pass between viruses so a virus may quickly acquire a genetic variation that has previously evolved and already exists in the viral reservoir (the pool of viruses circulating in a population). Unlike sporadic mutations, recombination reflects the acquisition of genetic material that has withstood the Darwinian test of time. Compared to sporadic mutation, recombination is a quicker, non-random mechanism for genetic change.

Changes in the H1N1 viral genome are natural. The viral reservoir consists of wild-type viruses (the predominant viruses) and low levels of variants carrying a variety of different sequences called “polymorphisms.” While recombination is not the currently favored theory regarding how flu viruses evolve, Dr. Niman believes it is the correct theory. The theory of recombination as a mechanism for genetic change has led to accurate predictions about how the flu virus would evolve as infection rates increase. As the size of the viral reservoir continues to expand, viruses with genetic differences, “polymorphisms,” become more evident.

Ukraine Outbreak

The outbreak in Ukraine was initially described in many media reports as a new lung-blackening “mystery disease,” leading to many false and misleading Internet stories. According to Dr. Niman, it was clear from the start that H1N1 was killing an unusually high number of previously healthy young adults… (See Flu News: D225G Follow-up)

Dr. Niman wrote a number of commentaries on the rising death toll and the need to make the sequences public. He predicted the deaths would be associated with a receptor binding domain change in the wild-type H1N1 virus (the predominant virus) to…
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Flu News: D225G Follow-up

In case you missed my latest update on the flu, I’ve added to it here. – Ilene

Flu News: D225G Follow-up

By Ilene with guest expert Dr. Henry Niman

Swine Flu Precautions Continue For International Travellers

Dr. Henry Niman heads the research company Recombinomics Inc. Recombinomics has a small group of researchers who analyze the sequence data from viral samples isolated from patients diagnosed with swine flu.

I spoke with Dr. Niman last week about the evolution of the H1N1 virus as it circulates through the world’s population. These changes are natural—and Dr. Niman’s research on the subject allowed him to predict how the virus would change as infection rates increase and time goes on. The outbreak in Ukraine was initially described in many media reports as a new lung-blackening "mystery disease," leading to many false and misleading Internet stories. According to Dr. Niman, it was clear from the start that H1N1 was killing an unusually high number of previously healthy young adults. 

H1N1 infection seemed to cause more severe illness in Ukraine, and Ukraine officials asked the WHO for assistance. The WHO interfaced with Ukraine labs in Kiev and sent groups into western Ukraine to survey the problem and gather information. As part of the investigation, the WHO sent samples to Mill Hill in London, one of several regional centers that performs genetic analysis for the WHO.

Subsequently, the WHO issued several non-informative reports but held the sequences at Mill Hill for analysis. Dr. Niman wrote a number of commentaries on the rising death toll and the need to make the sequences public. He predicted the deaths would be associated with a receptor binding domain change in the wild-type H1N1 virus (the predominant virus) to a variant form, characterized by the D225G genetic marker. Wild-type H1N1 has a D at position 225 of the viral protein Hemagglutinin (HA), and is referred to as D225. The variant protein, D225G, has a genetic change causing a change in position 225 of the protein. "D" is the symbol for the aspartic acid which is present at position 225 of the wild-type protein. Glycine, symbol G, replaces aspartic acid in D225G variants. Hemagglutinin is one of two surface proteins projecting out from the surface of the virus. The function of the HA protein is to bind viral particles to susceptible cells in the host animal.

The…
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Sen. Lindsey Graham, R.-S.C., left, and Senate Majority Leader Mitch McConnell pictured Sept. 26, 2017 before the vote on Graham’s bill to gut Obamacare. Like others before it, the bill failed. Andrew Harnik/AP

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