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Neutralización de genotipos del virus del sarampión: identificación y caracterización en la hemaglutinina viral de epitopos neutralizantes de amplio espectro e inmunodominantes en la infección natural
Title (trans.)
Identification and characterization of measles virus genotypes neutralization epitopes: in search of natural infection immunodominant and broad spectrum neutralizing hemagglutinin epitopesAuthor
Muñoz Alía, Miguel ÁngelAdvisor
Fernández Muñoz, RafaelEntity
UAM. Departamento de BiologíaDate
2014-07-17Subjects
Sarampión - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología. Fecha de lectura: 17-07-2014Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Measles
virus
(MeV)
is
the
most
contagious
respiratory
infectious
disease
known
in
humans
and
the
leading
cause
of
vaccine-‐preventable
deaths
in
children
worldwide.
An
attenuated
vaccine
is
in
use,
but
no
therapeutic
or
prophylactic
antibodies
or
MeV
antivirals
are
currently
available.
Protection
against
MeV
is
associated
with
the
development
of
neutralizing
antibodies
(nMoAb)
that
preferentially
recognize
the
measles
virus
hemagglutinin
protein
(MVH).
Although
a
single
serotype
was
described,
24
MeV
genotypes
have
been
identified
with
different
geographical
and
temporal
distribution
showing
characteristic
nucleotide
and
amino
acid
differences
in
the
several
genes.
Most
of
the
variability,
as
determined
in
48
MeV
primary
isolates
along
a
six-‐month-‐epidemic
outbreak
in
Madrid
caused
by
one
foreign
person
infected
with
MeV
genotype
B3.1,
appeared
in
the
MVH
gene
(up
to
0,38%)
where
we
have
estimated
the
rate
of
nucleotide
substitution
to
be
7,27x10-‐6
per
site
per
day
(95%
confidence
interval,
3,09x10-‐6
–
1,23x10-‐5).
The
effect
of
the
inter-‐
and
intra-‐genotype
variations
in
the
MVH
from
MeV
genotypes
that
have
circulated
in
the
Madrid
region
for
the
last
50
years
to
date
(genotypes
A,
B3.1,
C2,
D4.1,
D4.4,
D6,
D7,
D8,
D9,
F,
G3,
H1),
were
functionally
and
structurally
characterized
by
several
murine
nMoAbs
targeting
distinct
epitopes
and
nMoAb
neutralization-‐escape
mutant
viruses.
Our
data
revealed
neutralizing
genotype-‐specific
epitopes
on
the
MVH
and
significant
differences
in
the
kinetics
rates
and
affinity
of
the
nMoAb
to
the
MVH
by
Surface
Plasmon
Resonance
that
correlate
with
the
neutralization
sensitivities
of
the
corresponding
virus
strain.
By
means
of
a
labelled
MoAb
binding
competition
radioimmunoassay
(RIA)
to
MVH
in
its
native
oligomeric
structure
complexed
with
MVF
by
post-‐measles
sera,
developed
in
our
laboratory,
we
have
found
that
the
genotype-‐specific
epitopes
are
immunogenic
in
natural
infection
and
may
elicit
long-‐term
B
memory.
We
have
identified
two
potent
broadly
neutralizing
epitopes
conserved
in
every
MeV
genotype.
One
is
located
in
one
MVH
receptor-‐binding
site
and
the
other
is
at
the
MVH
monomers
interface.
We
have
assayed
comparative
binding
of
each
of
MeV
receptors
CD46,
CD150
(SLAM)
and
nectin-‐4
to
cloned
MVH
protein
from
different
MeV
genotypes
from
acute
measles
and
brain
from
deceased
Subacute
Sclerosing
Panencephalitis
patients,
and
found
some
differences
among
genotypes
cohere
with
amino-‐acid
sequences
in
receptor-‐binding
sites.
This
information
could
be
applied
to
design
better
measles
vaccines,
potent
broad-‐
spectrum
prophylactic
and
therapeutic
anti-‐MeV
MoAbs,
and
to
dampen
pre-‐existent
MeV-‐
specific
antibodies
for
MeV-‐based
gene
therapy
and
oncolytic
cancer
therapies.
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