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Study Outlines Bird Flu Virus Changes Needed For Mammalian Transmission

NEW YORK (GenomeWeb) – In a long-awaited study appearing online today in Science, an Erasmus Medical Center-led team provide results from their study looking at the "bird flu," or avian H5N1 influenza A, virus' ability to morph into a form that is transmissible between mammals — along with the genetic alterations that accompany this transformation.

"The H5N1 bird flu virus can acquire the ability of aerosol transmission between mammals," Ron Fouchier, a virology researcher at Erasmus Medical Center, said during a telephone press briefing yesterday. "We showed that as [few] as five mutations but certainly less than 10 are sufficient to make H5N1 virus airborne."

The study, the publication of which had been forestalled for several months owing for biosecurity and biosafety concerns, comes on the heels of a related study by Japanese researchers published online in Nature this May. That paper described reassortment events between the H5N1 bird flu virus and the 2009 H1N1 pandemic swine flu virus that led to the development of influenza A H5 viruses that could hop between ferrets via respiratory droplets.

In their own efforts to better understand how avian H5N1 influenza A viruses could attain airborne transmission in mammals, Fouchier and his colleagues introduced three targeted mutations to the A/H5N1 strain called A/Indonesia/5/2005 based on their knowledge of mutations present in past flu pandemics.

They then used the genetically modified strain to infect ferrets, tracking the viruses' ability to move between animals via aerosols or respiratory droplets and looking at the additional mutations it acquired in the process.

Sanger sequencing analyses of mammalian-transmissible H5N1 influenza A viruses isolated after 10 passages in ferrets indicate that these alterations include new mutations to the same genes that the team targeted initially — the gene coding for a hemagglutinin surface protein that binds host receptors and the PB2 polymerase gene — as well as mutations affecting other genes.

"Given the large numbers of [highly pathogenic avian influenza] A/H5N1 virus-infected hosts globally, the high viral mutation rate, and the apparent lack of detrimental effects on fitness of the mutations that confer airborne transmission, it may simply be a matter of chance and time before a human-to-human transmissible A/H5N1 virus emerges," authors of the study cautioned.

Together, both the new study and last month's Nature study "answer the long standing and important question of whether it's possible for H5N1 viruses to transmit by an airborne route between mammals," according to University of Cambridge zoology researcher Derek Smith, who is also affiliated with Erasmus Medical Center, and the World Health Organization's Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Disease.

"One of the next key questions is, 'How likely is it that such viruses could evolve in nature?,'" said Smith, who co-authored the Science study describing the development of mammalian transmissible A/H5N1 strains.

In a second study, also appearing in Science today, Smith and his co-authors began exploring that question in more detail, looking at whether the mutations identified in the ferret paper are present in A/H5N1 virus sequences found in surveillance data so far.

"Leveraging the worldwide surveillance of H5 [avian flu viruses] over 15 years, we analyzed over 4,000 strains of influenza virus, [and] the sequences from these strains," Smith told reporters. "And we found that two of the mutations are already seen frequently, including in combination with each other."

For that study, researchers also used mathematical modeling to explore viral evolution patterns within and between hosts — an analysis that suggested it is possible for flu viruses to acquire three mutations in a single host.

While the likelihood of such an occurrence is still unclear, Smith said, "The path is now clear for what needs to happen next, in terms of the steps that have to be taken to more accurately assess the risks of these viruses emerging in nature."

"Over the past decade, we have closely monitored the H5N1 influenza virus," National Institute of Allergy and Infectious Diseases Director Anthony Fauci said during yesterday's telebriefing.

"Given the possibility that the virus could become more easily transmissible to humans and spread from person-to-person, the scientific community, with [National Institutes of Health] funding has appropriately intensified its efforts to better understand the virus and how it may evolve in an attempt to stay ahead of a potential pandemic," added Fauci, who co-authored a related Science policy forum with NIH Director Francis Collins.

In the commentary, Fauci and Collins discussed the rationale behind influenza research, including controversial studies that involve modifying naturally occurring H5N1 strains. They also touched on existing and anticipated US government policies regarding so-called "dual-use research of concern" in the life sciences — research that is expected to be beneficial, but which could pose safety, security, or environmental risks if misused.

Other H5N1-related commentaries in today's Science studies dealt with topics ranging from influenza pandemic preparedness and vaccine development strategies to further discussion of dual-use research as well as related risk-benefit analyses and cybersecurity issues.

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