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PostPosted: Wed Mar 24, 2010 2:13 pm 
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http://www.physorg.com/news188657864.html


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PostPosted: Wed Mar 24, 2010 2:25 pm 
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Researchers have found that the H1N1 swine influenza virus that last year caused the first human pandemic in 4 decades shares an important surface protein with the virus responsible for the 1918 flu, the deadliest in human history. This newfound similarity answers many mysteries about the 2009 pandemic, including why it largely spared the elderly.

A study published 24 March in Science Translational Medicine shows that even though nearly a century separates the widespread circulation of the two viruses in humans, mice given a vaccine against the 1918 strain produced antibodies that "neutralized" the novel 2009 strain. When the team flipped the experiment and used a 2009 pandemic vaccine in mice, the immune response stopped the 1918 virus. "We kind of did a double take," says virologist Gary Nabel, head of the VaccineResearchCenter at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, and the lead researcher on the project. "It was an unexpected finding, but it all makes sense when you look at the data collectively."

Influenza and the human body are like opposing Cold War spies, with the virus repeatedly donning new disguises, and the human immune system racing to foil each incarnation. The surface protein, hemagglutinin (HA), is the virus's main quick-change artist, easily adapting mutations to alter the way it looks to the immune system. Antibodies produced by the immune system, in turn, try to neutralize the various HAs by binding to them, blocking the virus from entering cells. As a rule, influenza viruses change so quickly that a vaccine against a regular "seasonal" strain circulating one year may have little impact against a similar strain a few years later. Yet the HA proteins on the 1918 and 2009 pandemic viruses look remarkably similar in close analyses done in both Nabel's study and a separate one published online this week by Science that includes x-ray crystallographic data. These two reports also clarify the evolution of seasonal strains in the decades between the two pandemics.

The two studies focus on the top part, or the head, of the HA, which is the business end of the protein when it comes to the infection process. Each research group calculated that the amino acids in the head of the two pandemic HAs were only about 80% similar, which is roughly the divergence seen between two seasonal strains. This would suggest that antibodies against the 1918 and 2009 pandemic strains would not cross neutralize. How then to explain the mouse results?

Nabel and colleagues took a closer look at the HA protein. A discrete region of the HA's tip that plays a critical role in binding to cells, they found, has a 95% similarity in amino acid sequence between the old and new pandemic strains. Comparisons between seasonal and the pandemic strains in this region found less than 70% similarity.

In the second study, a team led by structural biologist Ian Wilson of the Scripps Research Institute in San Diego, California, went further, linking the amino acid sequence analysis to the three-dimensional structure. Wilson's group crystallized the 1918 and 2009 pandemic viruses and showed that the HA heads had distinctly similar shapes. "The closest related structure that we have to the current 2009 swine flu is the 1918 structure," says Wilson.

Both the Wilson and the Nabel studies show that the HAs of the two pandemic strains also look markedly different from seasonal viruses when it comes to sugars on their surfaces. All seasonal strains have at least two "glycosylation" sites where sugars attach to the top of their HAs, whereas both the pandemic strains are bald. "The absence of glycosylation at the top of these molecules is making a huge difference in the immune response," says U.S. Centers for Disease Control and Prevention virologist Ruben Donis, who was not involved with the study. Specifically, the antibody that works against the bald 1918 virus stops the bald 2009 incarnation but does nothing to the sugared-up relatives that circulated in between those two pandemics.

The new studies are helping to clarify how influenza viruses have used sugars in their evolution since 1918, says U.S. National Institute of Allergy and Infectious Diseases virologist Jeffrey Taubenberger, a leading investigator of that devastating pandemic. "All the influenza viruses in humans are descendants of the 1918 virus," says Taubenberger, who published mouse experiments 8 March online in Influenza and Other Respiratory Viruses that similarly show how the 1918 virus protects against the 2009 pandemic strain. "Over the last 91 years, we've been in one large 1918 pandemic era."

Mutations in the HA can affect the structure of the protein and the clouds of sugars that surround it. By analyzing the difference in the earliest available seasonal HAs from 1933 to 2009, Nabel's group found that some amino acid mutations restructured the HA head, but after that the bald virus started accumulating new glycosylation sites. Nabel posits that the bald 1918 virus could tolerate only a limited number of amino acid changes that altered its structure. "At a certain point, there's a fitness cost for adopting a new mutation, so the virus says, 'What else can I do?' " says Nabel.

In a perspective he co-authored in Science Translational Medicine about the Nabel study Rino Rappuoli, head of vaccine research at Novartis Vaccines & Diagnostics in Siena, Italy,says elderly people were spared in the recent swine flu pandemic because they were exposed to the 1918 virus or its sugar-free descendants that subsequently circulated for a few decades and developed a lifelong antibody response to the bald viruses. "Evolution does not necessarily bring new things," says Rappuoli. "It sometimes brings things back."

For full coverage, see the 26 March issue of Science.
http://news.sciencemag.org/sciencenow/2 ... html?rss=1

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PostPosted: Wed Mar 24, 2010 2:28 pm 
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niman wrote:
"Evolution does not necessarily bring new things," says Rappuoli. "It sometimes brings things back."

For full coverage, see the 26 March issue of Science.
http://news.sciencemag.org/sciencenow/2 ... html?rss=1

Which is why recombination is called "elegant evolution".

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PostPosted: Wed Mar 24, 2010 2:30 pm 
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niman wrote:
The two studies focus on the top part, or the head, of the HA, which is the business end of the protein when it comes to the infection process. Each research group calculated that the amino acids in the head of the two pandemic HAs were only about 80% similar, which is roughly the divergence seen between two seasonal strains. This would suggest that antibodies against the 1918 and 2009 pandemic strains would not cross neutralize. How then to explain the mouse results?

Nabel and colleagues took a closer look at the HA protein. A discrete region of the HA's tip that plays a critical role in binding to cells, they found, has a 95% similarity in amino acid sequence between the old and new pandemic strains. Comparisons between seasonal and the pandemic strains in this region found less than 70% similarity.


For full coverage, see the 26 March issue of Science.
http://news.sciencemag.org/sciencenow/2 ... html?rss=1

How do you spell D225G?

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PostPosted: Wed Mar 24, 2010 2:31 pm 
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Not new. 1918 was a swine/human H1N1 recombinant

http://www.recombinomics.com/News/12140 ... demic.html

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PostPosted: Wed Mar 24, 2010 3:23 pm 
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The absence of a sugary viral shield could explain why immune responses to the 1918 influenza virus also work against the 2009 H1N1 (swine flu) pandemic strain.

Researchers have found that the two viruses, although separated in time by nearly a century, are structurally similar in a region that is recognized by the immune system. In seasonal flu viruses, that region — a part of the haemagglutinin protein often used to create flu vaccines — is dotted with sugar molecules; however, the two pandemic flu strains lack this sweet spot. This might explain why seasonal flu vaccines don't protect against swine flu.

The results, published today in Science1 and Science Translational Medicine2, could also explain an unusual feature of swine flu: its tendency to hit the young hardest, rather than the elderly population that is usually most at risk from flu viruses.

Scientists thought that older people might have benefited from exposure to the 1918 flu virus and its immediate descendants. That previous exposure seems to have produced antibodies that cross-react with the 2009 strain. Indeed, earlier this year, researchers identified antibodies from 1918 flu survivors that could target both the 1918 and the 2009 viruses3. But it was unclear exactly how the immune responses to the two viruses overlapped.

The sweet spot
Now, structural biologist Ian Wilson of the Scripps Research Institute in La Jolla, California, and his colleagues have determined the structure of one such antibody that is bound to the haemagglutinin protein from each pandemic virus1. They found that the region bound by the antibody was highly similar in both pandemic viruses — and that it lacked the sugar molecules found in seasonal flu strains.


Structure of the influenza virus hemagglutinin from pandemic and seasonal strains, highlighting the antibody (red) and sugar (blue) binding sites.
Jeffrey C. Boyington and Gary J. NabelThese sugar molecules can help the seasonal virus to elude capture by the immune system by providing a barrier that prevents antibodies from accessing the protein underneath. And because the sugars are present on human proteins as well, the immune system is less likely to view them as a threat. It is a clever strategy harnessed by many other viruses, including HIV.

In another study, Gary Nabel, a virologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and his collaborators traced the evolution of this sugar signature in seasonal and pandemic H1N1 viruses. They found that the sugars began to appear by the 1940s, and by the 1980s, nearly all of the seasonal flu viruses were adorned with the molecules2. But the sugars are all but absent from the pandemic virus.

These data suggest that flu viruses have gone full circle, says Nabel. "When the virus first appeared, it didn't need that shielding because there weren't any human antibodies to it," he says. But when antibodies appeared that targeted that region, there was an advantage for the virus to hide it behind a sugar shield. By the time the 2009 pandemic hit, most of the population no longer made these antibodies, and the shield was no longer needed.

Thinking ahead
The results suggest that the cycle may now begin anew. Sugars could emerge again in the 2009 pandemic strain, as more of the population is exposed to the virus and begins to produce antibodies against it. Indeed, Nabel and his team have recently found the first evidence of that: four new strains of the 2009 swine flu virus, three from Russia and one from China, have acquired a mutation that would allow a sugar to be attached to the conserved region of the haemagglutinin protein2.

With that in mind, Nabel suggests that future vaccines against the 2009 strain should perhaps be made using viruses that bear sugars on the conserved region of their haemagglutinin protein. Animal studies by his team suggest that such vaccines would work against viruses with or without the sugar molecules.

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But he cautions that additional work would need to be done before committing vaccine production to this strategy. "The tricky part is, we don't know that this mutation alone is going to be the thing that's going to give rise to the next-generation virus," he says.

Infectious-disease specialist Jonathan McCullers, of St Jude Children's Research Hospital in Memphis, Tennessee, agrees. Pandemic flu strains often add more sugar molecules the longer they circulate in humans, so it is likely that the 2009 H1N1 strain will shift to a more heavily coated virus over time, he notes.

But McCullers adds that there is a limit to how heavily coated the strain used to make a vaccine should be, because each added sugar obscures another region of the virus from the immune system. Too many sugars could make it difficult to mount an effective immune response to the vaccine, he points out.

References
1.Xu, R. et al. Science advance online publication doi:10.1126/science.1186430 (2010).
2.Wei, C.-J. et al. Science Trans. Med. 2, 24ra21 (2010).
3.Krause, J. C. et al. J. Virol. 84, 3127-3130 (2010).

http://www.nature.com/news/2010/100324/ ... rticles%29

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PostPosted: Wed Mar 24, 2010 10:49 pm 
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niman wrote:

In the second study, a team led by structural biologist Ian Wilson of the Scripps Research Institute in San Diego, California, went further, linking the amino acid sequence analysis to the three-dimensional structure. Wilson's group crystallized the 1918 and 2009 pandemic viruses and showed that the HA heads had distinctly similar shapes. "The closest related structure that we have to the current 2009 swine flu is the 1918 structure," says Wilson.

For full coverage, see the 26 March issue of Science.
http://news.sciencemag.org/sciencenow/2 ... html?rss=1

The structure of an antigenic determinant in a protein

Ian A. Wilson, Henry L. Niman, Richard A. Houghten, Andrew R. Cherenson, Michael L. Connolly and Richard A. Lerner

Department of Molecular Biology Research Institute of Scripps Clinic, La Jolla, California, 92037, USA

Received 3 January 1984; Revised 9 March 1984. Available online 29 April 2004.

Abstract
The immunogenic and antigenic determinants of a synthetic peptide and the corresponding antigenic determinants in the parent protein have been elucidated. Four determinants have been defined by reactivity of a large panel of antipeptide monoclonal antibodies with short, overlapping peptides (7–28 amino acids), the immunizing peptide (36 amino acids), and the intact parent protein (the influenza virus hemagglutinin, HA). The majority of the antipeptide antibodies that also react strongly with the intact protein recognize one specific nine amino acid sequence. This immunodominant peptide determinant is located in the subunit interface in the HA trimeric structure. The relative inaccessibility of this site implies that antibody binding to the protein is to a more unfolded HA conformation. This antigenic determinant differs from those previously described for the hemagglutinin and clearly demonstrates the ability of synthetic peptides to generate antibodies that interact with regions of the protein not immunogenic or generally accessible when the protein is the immunogen.

Cell
Volume 37, Issue 3, July 1984, Pages 767-778
http://www.sciencedirect.com/science?_o ... c63bfa08be

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PostPosted: Wed Mar 24, 2010 11:34 pm 
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:thumbsup: Dr Niman et al.


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PostPosted: Thu Mar 25, 2010 7:17 am 
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Tex wrote:
:thumbsup: Dr Niman et al.

Actually, the original paper would be Niman et al:

Proc Natl Acad Sci U S A. 1983 Aug;80(16):4949-53.

Generation of protein-reactive antibodies by short peptides is an event of high frequency: implications for the structural basis of immune recognition.
Niman HL, Houghten RA, Walker LE, Reisfeld RA, Wilson IA, Hogle JM, Lerner RA.

Recent studies have shown that chemically synthesized small peptides can induce antibodies that often react with intact proteins regardless of their position in the folded molecule. These findings are difficult to explain in view of the experimental and theoretical data which suggest that in the absence of forces provided by the folded protein, small peptides in aqueous solution do not readily adopt stable structures. In order to rationalize the two findings, there has been general acceptance of a stochastic model which suggests that the multiple conformers of a peptide in solution induce sets of antibodies with a small percentage reactive with conformations shared by the folded protein. This stochastic model has become less tenable as the success rate for the generation of protein-reactive anti-peptide antibodies has grown. To test the stochastic model, we have used monoclonal anti-peptide antibodies as a way of estimating the frequency with which small peptides induce antibodies that react with folded proteins. We have made monoclonal antibodies to six chemically synthesized peptides from three proteins. The frequency with which the peptides induce protein-reactive antibodies is at least 4 orders of magnitude greater than expected from previous experimental work and vastly different from what would be predicted by calculating the possible number of peptide conformers in solution. These findings make the stochastic model less likely and lead to consideration of other models. Aside from their practical significance for generation of highly specific reagents, these findings may have important implications for the protein folding problem.

PMID: 6192445 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/6192445

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PostPosted: Fri Apr 02, 2010 12:00 pm 
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Commentary

http://www.recombinomics.com/News/04021 ... _2009.html

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