Controversial bird flu research finally published

After an unprecedented recommendation by a government review panel to block publication, a study that shows how the avian H5N1 influenza virus could become transmissible in mammals was published in full today in the journal Nature.

In December 2011, the National Science Advisory Board for Biosecurity recommended redacting critical information from the study. The unprecedented request was to withhold the methodologies used to make the virus transmissible and to not identify the mutations needed to make the virus transmissible in mammals. This month, the Advisory Board reversed itself, citing new information and manuscript revisions that more explicitly state the public health rationale for the work.

The publication caps an epic debate that pitted infectious diseases experts against flu and public health researchers who argued that publication was not only important, but also essential to informing preparedness for a virus that could evolve to cause a global pandemic.

The controversial research was conducted with ferrets, a widely accepted analog for influenza research because, when infected with the flu virus, they sneeze and cough, generating small droplets that can carry the virus from one animal to another, demonstrating transmissibility. The ferret respiratory tract also has cellular features similar to those found in humans.

The work shows that some viruses now circulating in nature require just four mutations to the hemagglutinin protein, which sits on the virus surface and enables it to bind to host cells, to become an even greater threat to human health. “Our study shows that relatively few amino acid mutations are sufficient for a virus with an avian H5 hemagglutinin to acquire the ability to transmit in mammals,” says Yoshihiro Kawaoka, the University of Wisconsin-Madison flu researcher whose work was at the center of the debate.

The Nature article explains that hemagglutinin utilizes a bulb-shaped structure called the “globular head” to bind to host cells at the time of infection. The amino acids in this portion of the hemagglutinin protein are like a combination that opens a locked cell. Without the right combination, the virus is unable to enter a host cell and cause infection. But with the continuing exchange of genetic information and consequent mutations, the virus can acquire the molecular features it requires to make it more infectious.

Kawaoka adds that a subset of the mutations necessary for mammalian transmission have already been detected in some viruses circulating in poultry flocks in Egypt and parts of Southeast Asia. “Because flu viruses in nature are constantly changing as they circulate and easily swap genes with other flu viruses, the possibility of circulating H5N1 viruses hitting the right combination of mutations and becoming a much bigger threat to human health is greater than many experts believed,” he warns. “We have found that relatively few mutations enable this virus to transmit in mammals. These same mutations have the potential to occur in nature.”

Whether or not the H5N1 viruses currently circulating in the world can easily acquire the additional mutations needed to cause a pandemic is an open question, according to Kawaoka: “It is hard to predict. The additional mutations may emerge as the virus continues to circulate.”

Kawaoka believes the new work will aid those who monitor flu outbreaks and could provide a critical early warning. “Should surveillance activities identify flu strains accumulating additional key mutations, these emerging viruses should then be priority candidates for vaccine development and antiviral evaluation,” he said.

In addition to demonstrating mammalian transmissibility, Kawaoka’s results showed the experimental mutant virus could be controlled by already available medical countermeasures. An existing H5N1 vaccine as well as the antiviral drug oseltamivir (Tamiflu) both proved effective.

“This study has significant public health benefits and contributes to our understanding of this important pathogen. By identifying mutations that facilitate transmission among mammals, those whose job it is to monitor viruses circulating in nature can look for these mutations so measures can be taken to effectively protect human health,” Kawaoka concluded.

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Source: University of Wisconsin-Madison

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