Reason for propagation of resistant flu viruses discovered

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With influenza Tamiflu counted as an universal weapon. However, the drug has his best time apparently behind itself: More and more viruses are resistant to it. Researchers examined the genotype of the causes and discovered determining changes.
US researchers have discovered mutations in the genotype of flu viruses which are behind the propagation of resistant causes. In the influenza season 2007/2008 it had come worldwide to the numerous cases in which the drug Tamiflu with the active substance Oseltamivir helped no more. The group around the Nobel Prize Laureate David Baltimore hopes that her knowledge serves to discover the signs of a future drug resistance with certain viruses.
The scientists of the California institutes of Technology (Caltech) in Pasadena present her results in the US-professional journal "Science".



Flu viruses are extreme wandlungsf?higGrippeviren belong to the most versatile causes. Now the team around Baltimore examined H1N1 viruses which released the pork influenza and also the Spanish influenza of 1918. The viruses need the enzyme Neuraminidase for her propagation to escape after the increase of her mother's cells. Oseltamivir restrains the Neuraminidase. Already since 1998 the mutant Influenza examined now A virus is known. Responsibly for the drug resistance the mutation H274Y is in the genetic code of the enzyme Neuraminidase, writes study author Jesse D. Bloom in "Science". Also this would be already identified for many years.

Nevertheless, in winter in 2007/2008 the resistant viruses have appeared suddenly everywhere. In the influenza season 2008/2009 has become clear that the current Oseltamivir could be applied no more with this seasonal influenza, one says in an accompanying piece to the study in "Science" .Das team around Bloom and Baltimore now discovered two other changes in the viruses Resistant to Oseltamivir namely likewise in the enzyme Neuraminidase. The both discovered mutations allowed the good increase. Also with the pork influenza it had come to the cases with which patients could not be treated successfully with Oseltamivir. Nevertheless, except Oseltamivir there are even other active substances against flu viruses.

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Re: Reason for propagation of resistant flu viruses discovered

Science 4 June 2010:
Vol. 328. no. 5983, pp. 1272 - 1275
DOI: 10.1126/science.1187816

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Reports
Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance
Jesse D. Bloom, Lizhi Ian Gong, David Baltimore*

The His274->Tyr274 (H274Y) mutation confers oseltamivir resistance on N1 influenza neuraminidase but had long been thought to compromise viral fitness. However, beginning in 2007?2008, viruses containing H274Y rapidly became predominant among human seasonal H1N1 isolates. We show that H274Y decreases the amount of neuraminidase that reaches the cell surface and that this defect can be counteracted by secondary mutations that also restore viral fitness. Two such mutations occurred in seasonal H1N1 shortly before the widespread appearance of H274Y. The evolution of oseltamivir resistance was therefore enabled by "permissive" mutations that allowed the virus to tolerate subsequent occurrences of H274Y. An understanding of this process may provide a basis for predicting the evolution of oseltamivir resistance in other influenza strains.

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

http://dx.doi.org/10.1126/science.1187816

 

[tetano]

Re: Reason for propagation of resistant flu viruses discovered

In the film Slumdog Millionaire, Jamal Malik, a teenager from Mumbai?s slums, wins India?s version of Who Wants to be a Millionaire? As the film continues, flashbacks reveal how events in Jamal?s life inadvertently furnished him with the knowledge to answer all fifteen questions and net the top prize. The film illustrates how some of life?s most useful events have no apparent value at first; their true worth lies in allowing us to exploit future opportunities. It?s a lesson that evolution also teaches, time and time again.

One such lesson has just been narrated by Jesse Bloom from the California Institute of Technology and stars the H1N1 flu virus. One of our main defences against this dangerous infection is the drug oseltamivir, better known as Tamiflu. The drug was generally effective against the H1N1 swine flu from last year?s pandemic, but it doesn?t work against seasonal strains of H1N1 that naturally circulate among humans. In 2007, the first signs of resistance emerged and within a year, virtually all strains of seasonal H1N1 were shrugging off Tamiflu. And we?ve only just worked out why this happened.

Tamiflu binds to a protein called neuraminidase, which covers the surface of the flu virus and allows it to break free from its host cell. Tamiflu worked by gumming up the business end of this protein, turning a host cell from a virus factory into a prison. The infecting viruses can replicate all they like but they can?t get out. But resistant strains have a mutation in their neuraminidase gene, which changes a single amino acid in the protein?s sequence. This changes the structure of the protein so that Tamiflu no longer sticks to it.

But this mutation, known as H274Y, is a double-edged sword. It allows the virus to shrug off Tamiflu, but it also changes the structure of neuraminidase so that the virus has trouble shunting it to its surface. The result is a strain, with half the necessary amount of neuraminidase ? it?s a less inviting target for Tamiflu but it?s also weak and feeble. When the first H1N1 viruses with this mutation were discovered in 1999, they were rubbish at infecting the cells of mice or ferrets. Scientists thought that this mutation was ?unlikely to be of clinical consequence?.

Clearly, they were wrong. The mutation spread like wildfire across the world, effectively neutralising one of our main weapons against seasonal flu. Now, Bloom has discovered how this supposedly crippling mutation conquered the globe ? it had help.

Bloom showed that some strains of H1N1 had already acquired two other mutations that eventually compensated for the harmful effects of the H274Y mutation. When these ?permissive mutations? first arose, they were fairly innocuous and may not have conferred any obvious advantages in their own right. But they sowed the seeds of resistance, allowing the virus to eventually pick up the H2747 mutation at no cost to itself. Like the random pieces of trivia in Slumdog Millionaire, these inoffensive events paved the way for a big future win.

Bloom sequenced the neuraminidase protein from a variety of seasonal H1N1 strains since 2006 and built up a family tree that charted which mutations they developed, and in what order. Two of these (V234M and R222Q for the technically minded) corrected the problems caused by H274Y, shifting the protein?s structure so that the right amount ends up at the virus?s surface. The combination of all three mutations produced a strain of flu that resisted Tamiflu and was just as good at infecting cells as normal strains. Compared to a strain that only had the resistance mutation, the triple-mutant grew 100 times better in cell cultures.

The story of H1N1 teaches us an important lesson. It means that some strains of virus are inherently better than others at evolving drug resistance and other important traits. Perhaps some mutations are already out there that could eventually pave the way for more virulent viruses, or ones that could jump the species barrier from other animals. For now, we know of two permissive mutations that allowed H1N1 to pick up Tamiflu resistance. In the future, it would behove us to monitor other lineages of flu ? particularly the recent pandemic strains ? for these same changes. If resistance crops up, it will most likely do so in these strains.


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