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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