March 27, 2003
Researchers Model Evolution of Influenza Virus
As health agencies around the world race to pinpoint the cause of
severe acute respiratory syndrome (SARS), researchers are reporting
success in developing a new theoretical model that shows how the
pressure exerted by the immune response of an infected population can
drive evolution of influenza virus.
The model does not aim to predict the emergence of new strains of
influenza, but it does suggest that a short-lived general immunity to
the virus might affect the virus's evolution. If immunologists can
understand the basis of such a response by influenza virus, then
vaccine designers might use that understanding to develop a vaccine
that offers more general immunity to the virus, said the
scientists.
“The principal question we were trying to address with this model is what biological factors determine the particular patterns we see in influenza evolution.”
Neil Ferguson
The researchers — led by Howard Hughes Medical Institute
international research scholar Neil M. Ferguson at Imperial College
London — published an article outlining their model in the March 27,
2003, issue of the journal Nature. Co-authors are Alison Galvani
from the University of California,at Berkeley, and Robin Bush from the
University of California, Irvine.
“The principal question we were trying to address with this
model is what biological factors determine the particular patterns we
see in influenza evolution,” said Ferguson. “We wanted to
understand the role of immunity in determining the competition between
different flu strains.”
Strains of flu virus differ from one another largely in the genes
that code for surface molecules called glycoproteins, which are the
primary targets of the body's immune system in defending against flu
viruses, said Ferguson. Evolutionary changes in immune response against
such “antigen” molecules are the reason that new vaccines
must be developed against emerging strains of virus.
A central mystery, said Ferguson, was why only a few new flu strains
emerge over time, replacing other strains that go extinct. Limitations
on genetic variance distinguish influenza from other RNA viruses such
as HIV and dengue fever, which exist in a wide range of variants, he
said.
“Given basic evolutionary theory, one might expect
naïvely that new influenza strains wouldn't necessarily drive the
others extinct, and the virus population would get more and more
diverse,” he said. “Understanding what stops that happening
was the key question posed in this study.”
To explore evolutionary dynamics, Ferguson and his colleagues
developed a computer-intensive mathematical model that simulated
mutation in individual genetic units, or codons, of the viral coat and
the effect of those changes on the transmission of the virus in human
populations. They included mutations that affected immune-related
properties of the virus, as well as those that did not. The researchers
hypothesized that modeling could yield information on the genetic
diversity of the virus population that would result from changes
induced by mutation.
The researchers ran their model with various assumptions about
mechanisms that might determine viral genetic diversity, and compared
the resulting simulated viral populations with real-world genetic
sequence data on populations of influenza strains.
“If you naively build a model which captures current
understanding in the flu research community of how the virus works,
then the model predicts increasing diversity through time - exactly
what is not seen,” said Ferguson.
“We therefore inferred that there must be some other form of
interaction between strains happening in the population,” he
said. “The best fit to genetic data was obtained when a
secondary, non-specific immune response was included in the model, on
top of the normal adaptive immune response which recognizes individual
virus strains. This secondary response gives a person complete
protection against nearly all variants of the influenza virus, but only
for a short period of time.” This kind of protection, said
Ferguson, would last only for perhaps weeks after infection, after
which it would fade, rendering a person vulnerable to reinfection with
a different viral strain.
Virologists had previously postulated that temporary, non-specific
immunity might exist “but it hasn't been thought of up until now
as being a very significant driver, either of influenza evolution or of
epidemiology. However, this work indicates that non-specific responses
probably have a critical effect on both influenza transmission and
evolution,” said Ferguson.
Since the mechanism of this kind of immunity remains unknown,
Ferguson adds that it remains to be seen whether it might provide the
basis of a more general influenza vaccine.
“If innate immunity is responsible, then exploiting this for
vaccine development might be difficult due to the negative clinical
consequences for the individual associated with inflammatory
responses,” said Ferguson. “However, if it's due to an
adaptive immune response recognizing other non-changing viral antigens,
then vaccines that target those antigens might have a longer-term
effect than the annual protection afforded by current vaccines,”
he said.
More generally, said Ferguson, this type of modeling offers basic
insights into the factors that drive influenza evolution that might
improve understanding of which dominant variants that are likely to
arise. “If we can understand in much more detail the biological
relationship between the genome of the virus and its antigenic
phenotype, then we'll be able to get to much more predictive
mathematical models of the evolution of the virus,” he said. He
emphasized that improved understanding will depend upon improved data
from more detailed global surveillance of all influenza variants, not
just the newly emerging pathogenic variants.
Ferguson said that the general approach to modeling that he and his
colleagues employ is also being adapted to understand the evolution of
other RNA viruses including HIV.
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