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 Scott
E. Hensley,
Ph.D.
Assistant Professor, Immunology
The Wistar Institute
Office Address:
The Wistar Institute
Room 276
3601 Spruce St.
Philadelphia, PA 19104
TEL 215-495-6864
LAB 215-495-6866
shensley@wistar.org
RESEARCH SUMMARY
Seasonal influenza virus poses a major threat to the human population, contributing
to over 30,000 annual deaths in the United States alone. Influenza virus
rapidly escapes pre-existing humoral immunity by accumulating mutations in
the viral surface proteins hemagglutinin (HA) and neuraminidase (NA). This
process, termed “antigenic drift”, creates antigenically distinct
viruses, making it difficult to predict which types of viruses will predominate
during any given flu season. Understanding the underlying mechanisms
that promote antigenic drift is a key scientific and public health challenge.
For decades, the leading hypothesis has posited that certain individuals mount
restricted neutralizing antibody responses that enable the virus to undergo sequential
selection. This established paradigm is largely based on in vitro and in
ovo studies that examined how influenza virus mutates in the presence of
monoclonal antibodies.
Revisiting a mouse model of antigenic drift established
in the 1950’s, we found that influenza virus rapidly accumulates HA mutations
that increase receptor binding avidity when confronted with polyclonal antibodies in
vivo. Passaging such mutant viruses in naïve mice selects for
viruses with additional HA mutations that restore receptor binding avidities
to wild-type levels. Surprisingly, many receptor-modulating mutations are
located in antigenic sites of HA, in many cases at a considerable distance from
the defined receptor binding pocket. Therefore, a major driving force of
influenza virus antigenic drift is likely related to how the virus interacts
with cellular receptors rather than how the virus interacts with individual antibodies.
All of these studies have been completed using a mouse-adapted influenza strain. Do
other subtypes of influenza virus utilize similar mechanisms? Does the
2009 pandemic H1N1 virus utilize similar mechanisms? We assume that most
individuals mount polyclonal antibody responses that support the growth of mutants
with high receptor binding avidity, but the reality is that very little is known
about the types of antibody repertoires elicited by natural influenza virus infection
and/or vaccines. Do certain individuals mount restricted antibody responses
or are multi-epitope responses the norm? At the end of the day, the best
way to combat antigenic drift is to create a broadly neutralizing vaccine that
is effective against antigenically diverse strains. Can increasing our
knowledge of influenza virus antibody repertoires allow us to design immunogens
that selectively elicit immune responses to conserved antigens?
It certainly is an exciting time to study influenza viruses! Potential
rotation projects include but are not limited to:
- Model antigenic drift of 2009 pandemic H1N1 virus in mice
- Determine immunodominance hierarchy of antibody responses induced by inactive
IAV vaccine
- Develop novel immunogens that elicit antibody responses to conserved regions
of HA
- Determine if receptor binding avidity influences antigenic drift of other
groups of viruses
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