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More Flu Viruses Around than Expected, Mutate in Unexpected Ways

By Pippa Wysong, Access Excellence

Rockville, MD (11/29/05)- Genetic studies of the human influenza virus are changing the understanding of how fast and how frequently viruses mutate. A series of studies recently published in the journals Nature and Science show that flu viruses swap genetic information far more frequently than was thought, and that there are even more versions of human flu than researchers suspected.

Plus, findings from a project that looked specifically at genetic information from the virus that caused the 1918 influenza pandemic may alter the basic understanding of how viruses adapt to different species. In fact, scientists now question their understanding of where viruses come from and what happens when they move between different species.

Samples of the 1918 virus came from sources that were frozen and stored for years.. "Studying the 1918 virus is difficult... it's something that happened about 90 years ago and we're basically doing archaeology at the molecular level," Jeffery Taubenberger, MD, PhD, told Access Excellence. He is chair of the Department of Molecular Pathology at the Armed Forces Institute of Pathology in Rockville, Maryland. Studying viruses from the past reveals details of how viruses evolve. Flu viruses change or mutate through a genetic swapping method microbiologists call reassortment, and have a segmented genome that allows them to swap genetic information easily. Genetic material is located on eight discrete segments of RNA rather than on one string.

"If an animal is co-infected with two different influenza strains at the same time, you could create a mixed virus by reassortment," said Dr. Taubenberger. This process explains the appearance of many avian source influenzas that have adapted to humans. For instance, the 1957 Asian and 1968 Hong Kong flu pandemics were both caused by reassortment in which the human adapted influenza virus acquired one or two new genes from a bird flu source. The genetic changes caused a protein on the surface of the virus (hemagglutinin) to be replaced. The resulting structure was different enough that people didn't have immunity to the new strain of virus, and it spread. However, the core part of the virus, which was adapted to humans, stayed the same. "It was thought this was the way pandemics form," he said.

In other words, something such as the H5N1 bird flu virus, which is currently circulating through Asia, could potentially lead to a pandemic through one of two possible mechanisms, not just the one previously believed way. "It could reassort with a human strain and cause a 1957-like pandemic, or it could alternately adapt (direcetly) to humans as happened in 1918," he said. The risk for a new virus emerging, he clarified, is greatest among people who interact closely with infected birds and are exposed to a high titre of virus, not from casual exposure.

Details about how flu viruses adapt to different species have emerged. "The 1918 virus has just a small handful of mutations in each of its genes that we think are very important in this process, and we're doing the experiments necessary to actually prove that," he said. Researchers found that when a bird virus shifts to a human-adapted one, two mutations are required in the hemagglutinin gene in order for it to bind well to receptors in human cells. Mutations in other specific genes are also needed. Understanding the molecular basis of how influenza viruses mutate to adapt to new hosts can lead to ways to prevent pandemics. It would help with surveillance, plus it would become possible to assess the risk different strains of influenza pose to people before they even reach the human population.

Another feature of the 1918 virus was that it was especially virulent, and the project is shedding light on just what features enhanced its virulence. "If you can identify particular mutations that account for a virus being very virulent in humans, that would be a great way to design a new class of drug, particularly to block that feature," Dr. Taubenberger said.

Origins of 1918 Virus A Mystery

Another unusual feature of the 1918 virus is that its origins are unknown. Unlike the 1957 and 1968 viruses which show genetic evidence of having come out of birds in Asia, the actual origins of the 1918 virus are uncertain. "The genetic sequences of the 1918 virus tell us that the donor of the 1918 virus was an influenza virus that was not in the gene pool of influenza viruses that we know about in birds now. It came from somewhere else... It's very possible there is a reservoir of influenza virus out in the world that actually gave rise to a virus that killed 50-million people. And we have no idea what that is or where it is," Dr. Taubenberger said.

He points out there are other viruses, such as ebola and the one that caused SARS, that have affected people yet the original host was never found. Dr. Taubenberger is now involved in studies looking at bird species not previously studied as possible hosts. "It started as a 1918 project and it's a much bigger project to try to understand how flu viruses move around between animals and occasionally cause pandemics in humans," he said.

Hundreds of Flu Virus Genomes Sequenced

Findings from the Influenza Genome Sequencing Project reveal several intriguing features about influenza viruses. The research is a joint project between the US National Institute of Allergy and Infectious Disease, and international partners. The goal is to sequence the genomes of thousands of influenza isolates, according to Steven Salzberg, PhD, professor and director of the Center for Bioinformatics and Computational Biology at the University of Maryland. At the time Access Excellence spoke to him, 539 genomes had been sequenced, using virus samples from New York, Tennessee and New Zealand. At the start of this year only seven complete genomes of H3N2 had been sequenced, now close to a hundred are sequenced monthly. By the end of 2006 there will be close to 1,500 more, he said.

Most of the flu viruses being sequenced belong to the H3N2 type, but a key finding is that there are multiple subpopulations of the flu. "Within H3N2 we found three distinct subtypes," he said. Distinguishing the subtypes was possible only through sequencing the genome. Plus, the three subtypes had different susceptibility to vaccines. "You have to figure out which subtypes are around, what they are and design your vaccine based on that," he said. Each year, flu vaccines are redesigned so they are effective against new mutations, though some years the vaccine is less effective than anticipated. Changes in the dominant subtype could be a key reason behind this.

Researchers found that the swapping of genetic information between viruses, or reassortment, happens more often than previously believed. "Our project is producing huge amounts of very detailed genetic information about the entire flu genome that was never around before," Dr. Salzberg said. The genome sequencing shows more details about reassortment than was known before. "If you don't do the whole genome, you can't see reassortment... You have to see the whole genome to see if all the segments are the same as those from other samples," he said. It's important to study numerous virus samples to see what the whole population is like, how diverse it is, how many subtypes there are, and what it does over time.

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