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Virology
Influenza evolution with little host selection
Influenza viruses undergo rapid antigenic evolution. Analysis of a large dataset of influenza virus sequences, using
host age as a proxy for immune experience, shows no evidence for immune positive selection driving antigenic
evolution in individual infected humans.
Katarina M. Braun and Thomas C. Friedrich
S
easonal influenza causes high morbidity
and mortality worldwide. In the United
States alone, the Centers for Disease
Control and Prevention has estimated that
influenza caused between 1.6 million and
9.7 million illnesses and 12,000 to 56,000
deaths between 2010 and 20141. Circulating
influenza viruses undergo rapid antigenic
evolution, necessitating frequent updates
to vaccine composition. However, the
evolutionary processes governing antigenic
change in influenza viruses remain difficult
to understand, let alone predict. For
example, it is unclear whether immune
positive selection acting within the host
plays a role in the evolution of seasonal
influenza viruses. Writing in Nature Ecology
& Evolution, Han et al.2 analyse a large
publicly available influenza virus sequence
dataset and report no signature of selective
pressures on viral antigenic evolution at the
level of individual infected hosts.
The influenza haemagglutinin (HA)
protein is responsible for viral attachment
to host cells and is thought to be the main
target of protective antibody responses.
Although previous work has shown how
specific amino acid substitutions in HA
affect antigenicity3, and how antigenic
variants spread globally4,5, we still cannot
predict which antigenic variants will emerge
in human populations, or when. Potential
antigenic variants can be detected at low
frequency in some infected humans, but
despite their apparent selective advantage,
such variants seem to be no more likely
to occur in vaccinated or unvaccinated
individuals6,7. Thus, fundamental questions
remain unresolved, including: How and
where are influenza antigenic variants
generated and selected? Do antigenic
variants ever evolve over the course of
infection in a single human?
Han et al. use a clever strategy to address
these questions on a broad scale. Noting
that antigenic variant influenza viruses can
be rapidly selected in vaccinated mice8, the
authors reason that they might detect the
imprint of immune selection on influenza
viruses infecting individual humans.
Nature Ecology & Evolution | www.nature.com/natecolevol
Using a set of more than 25,000 publicly
available HA sequences from all four human
influenza virus lineages (A/H1N1, A/H3N2,
B/Victoria, B/Yamagata), with associated
metadata, gathered from sites across the
world, they explore the relationship between
an individual’s immunological experience
and the presence of potential antigenic
variants in that individual. They predict that
mutations in HA should preferentially occur
in viruses infecting people with extensive
influenza exposure histories, whereas
such mutations would be rarer in viruses
infecting naïve people.
Based on previous studies of influenza
exposure histories, the authors postulate
that children under an age cutoff (generally
5 years) are largely immunologically naïve
to seasonal influenza, while adults above
a defined threshold (generally 25 years)
are likely to have significant influenza
immunity. Using a phylogenetic approach,
the authors identify ‘pairs’ of viruses that
are closely related genetically, but that
were isolated from different individuals.
Importantly, most of these virus pairs are
not linked epidemiologically — that is,
they do not represent instances of direct
transmission from one host to another —
but they are sufficiently closely related
to maximize the possibility of detecting
new mutations in an otherwise genetically
similar background. The authors categorize
virus pairs based on the order in which
they probably infected children or adults,
as deduced by tree topology: in child–adult
pairs, for example, a virus isolated from a
child paired with, and was ancestral to, a
virus isolated from an adult.
In this framework, the imprint of
immune selection would be observed as the
preferential occurrence of HA amino acid
substitutions in pairs that ‘end’ in an adult,
that is, in an immunologically experienced
host. But the authors find no such signal:
most nonsynonymous mutations they do
detect are equally likely to occur in pairs
that end in an adult or in a child. Specifically
considering mutations affecting important
phenotypes such as charge and protein
stability, the authors still find no evidence
that such mutations are more likely to
occur in end-in-adult pairs. The authors
perform several additional analyses to adjust
for potential confounding factors, such as
mutations that might arise when viruses
are grown in eggs prior to sequencing, or
changing immune function with age, and
again find no signature of individual level
selective pressures on HA evolution in this
large dataset.
As the authors note, an important caveat to
these studies is that a substantial proportion
of children under 5 years have already been
infected with influenza at least once, so age is
an imperfect proxy for immune status. Still,
findings from this study agree with other
smaller-scale investigations6,7, and support
the idea that influenza-specific immunity
does not play a strong role in selection
for viral antigenic variation in individual
infected people. But perhaps this should not
be surprising. As the authors note, influenza
is typically an acute infection, and there
may be little time for beneficial variants,
whether transmitted or arising de novo,
to become fixed in the virus population.
Seasonal influenza virus infections might be
founded by as few as one to two HA alleles;
founder effects associated with such a tight
transmission bottleneck might also reduce
the efficiency of selection and constrain viral
evolution9. So where do influenza antigenic
variants come from, and how are they
selected? Can we predict how this process will
unfold? New variants must arise in individual
infected hosts, but their survival and
transmission may be extremely uncommon.
Their successful emergence could depend
on hosts with rare phenotypes, like immune
compromise, which can allow for prolonged
infection10, and/or narrowly focused antibody
repertoires, which could lower the mutational
barrier to effective immune escape11.
Han and colleagues’ study provides a
framework by which global surveillance data
can be interrogated to search for patterns
of viral evolution in infected individuals,
and will help inform new laboratory studies
aimed at further elucidating the mechanisms
news & views
by which influenza viruses adapt under
immune pressure.
Katarina M. Braun1 and Thomas C. Friedrich1,2*
1
Department of Pathobiological Sciences, University
of Wisconsin School of Veterinary Medicine,
Madison, WI, USA. 2Wisconsin National Primate
Research Center, Madison, WI, USA.
*e-mail: thomasf@primate.wisc.edu
Published: xx xx xxxx
❐ https://doi.org/10.1038/s41559-018-0782-1
References
1. Rolfes, M. A. et al. Estimated Influenza Illnesses, Medical Visits,
Hospitalizations, and Deaths Averted by Vaccination in the United
States (Centers for Disease Control and Prevention, 2016).
2. Han, A. X., Maurer-Stroh, S. & Russell, C. A. Nat. Ecol. Evol.
https://doi.org/10.1038/s41559-018-0741-x (2018).
3. Koel, B. F. et al. Science 342, 976–979 (2013).
Nature Ecology & Evolution | www.nature.com/natecolevol
4. Rambaut, A. et al. Nature 453, 615–619 (2008).
5. Bedford, T. et al. Nature 523, 217–220 (2015).
6. Dinis, J. M. et al. J. Virol. 90, 3355–3365 (2016).
7. Debbink, K. et al. PLoS Pathog. 13, e1006194 (2017).
8. Hensley, S. E. et al. Science 326, 734–736 (2009).
9. McCrone, J. T. et al. eLife 7, e35962 (2018).
10. Xue, K. S. et al. eLife 6, e26875 (2017).
11. Davis, A. K. F. et al. J. Virol. 92, e00859-18 (2018).
Competing interests
The authors declare no competing interests.