Download Symbiotic Viruses of Eukaryots - Initial Set Up


Symbiotic
Viruses
of
Eukaryotes
Brett
Hoffman
[email protected]
Program
in
Vaccinology
and
Immunotherapeutics
School
of
Public
Health
and
Vaccine
and
Infectious
Disease
Organization
University
of
Saskatchewan
Canada
For:
Advanced
Virology
(VTMC833)
©
Brett
Hoffman
Abstract
Introduction
Polydnavirus
Background
PDV
genes
PDV
evolution
Endogenous
retroviruses
Background
Receptor
interference
Post­entry
blocks
Roles
in
host
physiology
Other
Symbiotic
viruses
Concluding
Remarks
References
Abstract
There
is
a
growing
body
of
research
that
suggests
numerous
eukaryotic
viral
infections
have
beneficial
effects
on
their
hosts.
This
is
in
contrast
to
the
view
of
viruses
as
obligate
1
intracellular
pathogens.
While
this
view
may
hold
true
for
the
vast
majority
of
viruses
of
eukaryotes
there
are
a
number
that
should
be
considered
intracellular
symbionts.
Polydnaviruses
(PDVs)
represent
an
example
of
these
symbiotic
viruses.
PDVs
are
produced
in
multiple
parasitic
wasp
species
and
are
injected
along
with
eggs
during
oviposition
into
a
lepidopteran
host.
Within
the
lepidopteran
host
viral
gene
expression
results
in
the
suppression
of
the
immune
response
which
is
necessary
for
the
survival
of
the
parasitoid
offspring.
Another
group
of
symbiotic
viruses
are
classified
as
endogenous
retroviruses
(ERVs).
Numerous
ERVs
have
been
found
in
several
eukaryotic
species
that
contain
open
reading
frames
which
express
proteins
capable
of
interfering
with
exogenous
retroviral
infection
either
by
blocking
entry
through
receptor
interference
or
blocking
steps
further
along
in
the
retroviral
lifecycle.
There
is
also
increasing
evidence
to
suggest
that
ERVs
may
play
important
roles
in
host
physiology.
In
sheep
ERV
encoded
envelope
glycoproteins
have
been
found
to
be
essential
in
the
process
of
placenta
morphogenesis.
This
finding
adds
further
support
for
a
role
of
ERV
derived
syncytins
in
this
process
within
humans.
Other
viral
infections
that
are
proposed
to
have
beneficial
impacts
on
their
hosts
include
latent
herpes
virus
infections.
These
latent
infections
may
provide
protection
against
pathogens
such
as
Listeria
monocytogenes
by
maintaining
the
innate
immune
system
in
a
heighted
state
of
activation
as
well
as
reducing
the
development
of
allergies.
Two
common
themes
emerge
when
investigating
the
mechanisms
through
which
these
symbiotic
viruses
benefit
the
host,
lateral
gene
transfer
via
integration
that
provides
the
host
with
new
genetic
material
encoding
for
novel
functions
and
the
modulation
of
the
immune
system
by
such
symbiotic
viruses.
2
Introduction
Viruses
are
typically
described
as
being
obligate
intracellular
pathogens
which
implies
that
all
viruses
are
pathogens
and
therefore
have
negative
or
at
best
benign
impacts
on
the
organisms
which
they
infect.
This
is
true
in
almost
all
cases
as
some
of
the
most
destructive
and
deadly
diseases
of
eukaryotes
are
caused
by
viral
infections.
Examples
include
the
devastating
hemorrhagic
fever
caused
by
Ebola
virus
as
well
as
smallpox
caused
by
Variola
virus
which
is
believed
to
have
killed
millions
of
people
until
its
eradication
in
the
1980’s
[58].
However,
there
are
examples
emerging
of
viruses
that
have
beneficial
effects
on
there
hosts,
playing
key
roles
in
their
resistance
to
pathogens
and
perhaps
even
essential
roles
in
host
physiology.
This
suggests
that
such
viruses
may
have
had
beneficial
impacts
on
the
evolution
of
the
host
species.
The
idea
of
viral
symbiosis
playing
a
key
role
in
host
evolution
was
popularized
by
Lynn
Margulis
[43].
She
proposed
that
symbiotic
relationships
are
the
driving
force
of
evolution
and
this
is
evident
in
the
widely
accepted
endosymbiotic
theory
which
describes
the
acquisition
of
the
chloroplast
and
mitochondria
by
the
ancestral
eukaryotic
cells
from
bacteria
[20,
43].
This
review
will
focus
on
examples
of
symbiotic
viruses
and
will
discuss
such
examples
as
the
polydnaviruses
(PDVs)
of
parasitic
wasps
which
are
crucial
for
the
suppression
of
the
immune
responses
in
the
lepidopteran
larvae
in
which
the
wasp
offspring
develops
[28].
Other
topics
to
be
discussed
include
the
roles
of
endogenous
retroviruses
in
protecting
their
hosts
from
exogenous
retroviral
infection
as
well
as
possible
roles
in
host
physiology.
The
possibility
of
some
viruses,
such
as
latent
herpes
virus,
to
act
as
symbionts
through
modulation
of
immune
responses
will
also
be
discussed
[6,
52].
3
Polydnavirus
Figure
1:
General
parasitoid
wasp
lifecycle
and
the
role
and
characteristics
of
Polydnavirus.
A)
Life
cycle
of
parasitoid
wasps
and
PDV.
(1)
Female
wasp
oviposits
single
or
multiple
eggs
along
with
numerous
PDV
particles
into
lepidopteran
larval
host.
The
PDV
genome
is
also
present
as
integrated
provirus
within
genome
of
parasitoid
egg.
(2)
PDVs
invade
multiple
tissues
within
lepidopteran
host
such
as
hemocytes
and
fat
body
cells
where
viral
gene
expression
occurs.
Viral
gene
products
suppress
the
lepidopteran
immune
responses
permitting
the
survival
of
the
parasitoid
egg
which
hatches
releasing
larva
that
begin
to
feed
and
develop.
(3)
While
lepidopteran
immune
responses
remain
suppressed
by
PDV
gene
products
parasitoid
larva
complete
juvenile
development
and
emerge
from
lepidopteran
host.
The
mature
larva
forms
a
cocoon
on
surface
of
host
and
undergoes
pupation.
During
pupation
the
integrated
PDV
present
in
wasp
genome
is
replicated,
excised
and
viral
particles
4
are
formed
in
the
calyx
cells
of
developing
female
wasps.
(4)
Adult
wasp
emerges
and
lepidopteran
host
dies.
PDV
particles
continue
to
be
produce
to
high
numbers
in
calyx
cells
of
adult
female
wasp.
Figure
adapted
from
references
[68,
69].
Background
Polydnaviruses
(PDVs)
are
atypical
viruses
that
are
found
in
numerous
endoparasitic
hymenoptera
(parasitoid
wasp)
species
and
are
essential
to
the
lifecycle
of
these
wasps
[20.
73].
PDVs
are
thus
referred
to
as
obligate
symbiotic
viruses
[20].
There
are
at
least
30,000
species
of
parasitoid
wasps
harboring
PDVs
[71].
The
polydnavirus
genome
that
is
found
within
virus
particles
is
unique
in
that
it
is
composed
of
a
series
of
circular
double
stranded
DNA
molecules
that
vary
in
size
from
4kb
to
41.5kb
[73].
In
addition
to
being
found
within
viral
particles
the
polydnavirus
genome
also
exists
as
a
stable
linear
provirus
molecule
that
is
integrated
within
the
parasitoid
genome
[72].
This
provirus
is
vertically
transmitted
by
female
wasps
to
their
offspring
in
a
typical
Mendelian
fashion
[25,
72].
These
viruses
are
not
known
to
cause
any
pathology
in
the
parasitoid
wasps
[72].
Each
PDV
from
a
given
wasp
species
is
genetically
unique
but
all
PDVs
share
a
similar
lifecycle
(Figure
1)
[73].
Virus
replication
occurs
exclusively
in
the
calyx
cells
of
the
female
wasp
ovary
where
the
integrated
copies
of
the
segmented
viral
genome
are
excised,
circularized,
replicated
and
packaged
[38].
The
exact
mechanism
by
which
PDV
genome
replication
occurs
is
still
unknown.
However,
it
is
thought
that
replication
may
occur
by
a
rolling‐circle
type
mechanism
in
which
the
excision
of
proviral
DNA
is
followed
by
amplification
of
circular
episomes
[36].
An
alternative
model
proposed
suggests
that
larger
chromosome
regions
are
amplified
prior
to
the
excision
of
individual
viral
segments
for
5
packaging
[36].
Once
virus
replication
and
packaging
is
complete,
virus
particles
are
released
into
the
lumen
of
the
oviduct
and
are
subsequently
injected
along
with
the
parasitoid
egg
into
a
lepidopteran
larval
host
during
oviposition
[38].
Within
the
lepidopteran
host
the
PDV
infects
multiple
tissues,
such
as
hemocytes
and
fat
body
cells.
Viral
genes
are
then
expressed
by
cellular
machinery
leading
to
the
suppression
of
the
lepidopteran
immune
response
as
well
as
disrupting
the
development
of
the
lepidopteran
host
[61].
With
the
immune
response
suppressed
the
parasitoid
egg/larvae
is
able
to
successfully
develop
within
the
haemocoele
of
the
lepidopteran
host
[72].
Upon
completion
of
larval
development
the
mature
larva
will
emerge
out
from
the
parasitized
host,
spin
a
cocoon,
pupate
and
emerge
as
adults
[72].
This
process
results
in
the
death
of
the
lepidopteran
larval
host
[72].
Unlike
a
typical
virus
infection,
PDVs
do
not
produce
a
replicative
infection
within
the
lepidopteran
host
[28].
Only
viral
gene
expression
occurs
in
this
host
while
no
viral
replication
or
particle
assembly
takes
place
[28].
Therefore
the
virus
is
only
propagated
by
its
passage
from
female
wasp
to
offspring
via
integration
within
the
wasp
genome
[71].
The
primary
immune
response
inhibited
by
PDVs
is
the
encapsulation
of
the
injected
parasitoid
eggs
by
hemocytes
within
the
lepidopteran
host
[69].
Multiple
classes
of
hemocytes,
with
granulocytes
and
plasmocytes
being
the
most
abundant,
are
involved
in
phagocytosis
of
small
particles
and
the
encapsulation
of
larger
objects
[30].
Granulocytes
are
thought
to
recognize
foreign
surfaces
and
release
cytokines
that
recruit
plasmocytes
to
the
surface
of
the
foreign
object,
in
this
case
the
parasitoid
egg
[59,
64].
The
plasmocytes
then
bind,
surround
and
encapsulate
the
foreign
object
[30].
This
process
typically
results
in
the
destruction
of
the
encapsulated
object
but
the
mechanism
of
destruction
is
unknown
6
[30].
It
has
been
shown
that
active
PDVs
are
required
to
inhibit
this
response
[20].
When
parasitoid
eggs
were
artificially
injected
without
the
PDV
or
with
UV
inactivated
PDV
the
eggs
were
destroyed
via
the
encapsulation
response
[20].
PDVs
belong
to
the
Polydnaviridae
family
of
viruses
and
are
further
divided
into
two
phylogenetically
unrelated
genera,
Bracovirus
(BV)
and
Ichnovirus
(IV)
that
are
associated
with
braconid
or
ichneumonid
parasitoid
wasps
respectively
[35,74].
PDVs
from
these
two
genera
differ
in
several
aspects
other
than
host
range
including
morphology
and
morphogenesis
as
well
as
envelope
structure
[38].
The
Bracovirus
PDV
nucleocapsid
is
cylindrical
whereas
the
Ichnovirus
PDVs
poses
a
lenticular
nucleocapsid,
and
in
both
genera
each
nucleocapsid
is
thought
to
contain
only
one
of
the
multiple
circular
dsDNA
segments
[7,
9,
38].
Single
or
multiple
Bracovirus
nucleocapsids
are
surrounded
by
a
single
envelope
membrane
and
these
virus
particles
are
released
into
the
lumen
of
the
oviduct
by
lysis
of
the
calyx
epithelial
cells
in
which
they
are
produced
[7,38].
Cell
lysis
does
not
cause
host
pathology
as
these
cells
are
continuously
renewed
[18].
By
contrast
Ichnovirus
nucleocapsids
are
typically
surrounded
individually
by
a
double
layer
envelope
membrane
and
are
released
from
the
calyx
cells
by
exocytosis
[38].
An
example
of
a
Bracovirus
is
Cotesia
plutellae
bracovirus
(CpBV)
of
C.plutellae
which
parasitizes
the
diamond
back
moth
(Plutella
xylostella)
(Figure
1B)
[35].
The
genome
of
CpBV
is
estimated
to
be
470kb
in
size,
made
up
of
at
least
27
non‐redundant
segments
ranging
in
size
from
6
to37kb
[35].
An
example
of
an
Ichnovirus
is
Campoletis
sonorensis
ichnovirus
(CsIV)
of
C.
sonorensis
that
parasitizes
the
tobacco
budworm
(Heliothis
viresccens)
(Figure
1C)
[22].
The
genome
of
CsIV
is
approximately
248kb
in
size
divided
into
24
unique
dsDNA
segments
that
range
in
size
from
6.1kb
to
19.5kb
[22].
7
Figure 1B. Characteristics
of
Cotesia
plutellae
Bracovirus,
a
polydnavirus
belonging
to
the
Bracovirus
genera
[35].
8
Figure
1C
Characteristics
of
Campoletis
sonorensis
Ichnovirus,
a
polydnavirus
belonging
to
the
Ichnovirus
genera
[22].
PDV
Genes
PDV
genes
share
a
number
of
features
that
are
typical
of
eukaryotic
genes
rather
than
viral
genes,
such
as
low
coding
density
(29%
for
CsIV),
the
presence
of
introns
and
homology
with
other
eukaryotic
genes
[9,36].
The
packaged
genome
of
PDV
also
completely
lacks
genes
encoding
for
viral
structural
proteins
or
proteins
required
for
virus
replication
[16].
The
genes
of
various
PDVs
are
organized
into
gene
families
based
on
sequence
homology
and
not
all
gene
families
are
found
in
each
species
[36,
71].
The
following
is
a
brief
review
of
some
of
the
better
characterized
and
conserved
gene
families
9
of
PDVs
(Table
1).
This
is
by
no
means
a
complete
list
of
the
numerous
PDV
gene
families
and
it
should
be
noted
that
there
have
been
many
PDV
genes
identified
that
share
no
known
homology
and
have
unknown
function
[28].
For
a
more
comprehensive
review
of
PDV
gene
families
please
refer
to
the
article
by
Kroemer
et
al.
[36].
Table
1.
Polydnavirus
gene
families
PDV
genes
Cys
gene
family
Example:
VHv1.1
of
CsIV
PTP
gene
family
Example:
ptp‐H2
of
MdBV
C‐type
lectin
gene
family
Example:
CpBV‐lectin
Rep
gene
family
Vinnexin
gene
family
Viral
Histone
H4
genes
Function
Linked
to
suppression
of
host
cellular
immunity
Interferes
with
encapsulation
response
and
disrupts
host
larval
growth
and
development
Linked
to
both
up
and
down
regulation
of
intracellular
signaling
Inhibits
phagocytosis
by
granulocytes/plasmocytes
and
induces
apoptosis
in
these
cells
Pattern
recognition
molecules
that
'mask'
molecular
patterns
from
host
c‐type
lectins
Binds
to
parasitoid
egg
on
same
sites
as
host
lectins
preventing
non‐self
recognition
of
egg
Function
not
determined,
possible
role
in
disruption
of
host
larval
growth
and
development
Function
not
determined,
possible
role
in
disruption
of
host
cellular
immunity
through
interference
with
cell
to
cell
signaling
Possible
role
in
epigentic
Description
Characterized
by
cysteine‐rich
motifs
and
conserved
exon
and
intron
structures
Share
homology
with
cellular
protein
tyrosine
phosphatases
Homologous
to
invertebrate
c‐type
lectins
Characterized
by
presence
of
highly
conserved
540bp
repeated
sequence
element
High
sequence
homology
with
invertebrate
innexin
genes
which
encode
for
gap
junction
proteins
High
sequence
homology
with
10
Example:
CpBV‐H4
host
histone
H4
genes
modification
of
chromatin
sturcture
resulting
in
alteration
of
gene
expression
Inhibition
of
cellular
immue
response
and
downregulates
gene
expression
of
host
H4
The
Cys
gene
family
is
characterized
by
cysteine‐rich
motifs
and
conserved
exon
and
intron
structures.
Members
of
this
gene
family
have
been
linked
to
suppression
of
host
cellular
immunity
[36,
39].
An
example
is
the
VHv1.1
protein
of
CsIV
which
was
found
to
bind
to
the
surface
of
hemocytes,
be
internalized
through
endocytosis,
and
interfere
with
encapsulation
by
an
unknown
mechanism
[39].
A
role
for
VHv1.1
in
the
inhibition
of
cellular
immunity
was
confirmed
by
the
disruption
of
the
encapsulation
response
against
wasp
eggs
following
in
vivo
expression
of
VHv1.1
from
a
recombinant
baculovirus
within
the
host
larvae
[76].
VHv1.1
has
also
been
observed
to
disrupt
host
larval
growth
and
development,
possibly
through
inhibition
of
host
protein
synthesis
[39].
This
is
supported
by
results
in
which
translation
of
fat
body
mRNAs
from
larval
hosts
were
reduced
in
the
presence
of
recombinant
VHv1.1
in
vitro
[72,
76].
Another
PDV
gene
family
is
the
protein
tyrosine
phosphatases,
which
have
be
linked
to
both
up
and
down
regulation
of
intracellular
signaling
through
dephosphorylation
of
tyrosine
residues
on
signaling
molecules
[31,
73].
The
Microplitis
demolitor
BV
gene
ptp­
H2
encodes
a
protein
tyrosine
phosphatase
that
has
been
shown
to
both
inhibit
phagocytosis
by
plasmocytes
and
granulocytes
[64].
ptp­H2
is
able
induce
apoptosis
of
these
immune
cells
and
is
thought
to
act
by
interfering
with
the
cell
cycle
[64].
11
The
C‐type
lectin
gene
family
is
homologous
to
invertebrate
c‐type
lectins
which
act
as
pattern
recognition
molecules
that
can
bind
surfaces
of
foreign
objects,
opsonizing
them
for
recognition
by
components
of
the
cellular
immune
system
[50].
It
is
thought
that
PDV
c‐
type
lectins
are
able
to
interfere
with
hemocyte
biding
to
parasitoid
eggs
by
competing
with
host
lectins
and
‘masking’
molecular
patterns,
thus
preventing
recognition
by
the
host
immune
response
[34,
55].
One
PDV
c‐type
lectin,
CpBV‐lectin,
binds
to
the
parasitoid
egg
on
the
same
sites
as
host
lectin
but
is
not
recognized
by
hemocytes
and
therefore
prevents
non‐self
recognition
of
the
parasitoid
egg,
resulting
in
the
prevention
of
encapsulation
[51].
The
Rep
gene
family
is
characterized
by
the
presence
of
a
highly
conserved
540bp
repeated
sequence
element
[26].
This
gene
family
represents
the
largest
PDV
gene
family
identified
thus
far
and
is
highly
conserved
among
Ichnoviruses;
however,
the
function
of
rep
gene
family
members
has
not
yet
been
determined
[24,
36].
In
a
recent
study,
rep
genes
were
found
to
be
predominately
expressed
in
the
cuticular
epithelium,
nervous
system
and
fat
body
cells
of
the
lepidopteran
host
as
opposed
to
within
hemocytes
[26].
This
suggests
that
the
rep
genes,
rather
than
playing
a
direct
role
in
the
suppression
of
the
immune
response
may
contribute
to
the
disruption
of
the
lepidopteran
host
larval
growth
and
development
[26].
Another
PDV
gene
family,
the
vinnexin
genes
display
high
sequence
homology
with
the
invertebrate
innexin
genes
which
encode
for
gap
junction
proteins
[26,
68].
Gap
junctions
are
used
for
cell
to
cell
communication
to
coordinate
multicellular
processes
[68].
Although
the
exact
role
that
vinnexins
play
is
unclear
it
is
thought
that
they
may
disrupt
12
host
cellular
immunity
by
interfering
with
cell
to
cell
signaling
between
hemocytes
during
encapsulation
resulting
in
an
ineffective
encapsulation
response
[68].
Another
group
of
PDV
genes
found
in
some
BV’s
share
high
sequence
similarity
with
host
histone
H4
[77].
In
eukaryotic
cells
chromosomal
DNA
is
wrapped
around
histone
particles
which
are
composed
of
two
molecules
of
each
H2A,
H2B,
H3
and
H4
[77].
Chromatin
structure
can
be
modified
by
the
action
of
histone
actyltransferase
and
histone
deacetylase
which
can
modify
the
histone
H4
amino‐terminal
tails
in
order
to
increase
or
restrict
access
to
DNA
sequences
therefore
modulating
gene
expression
[77].
An
example
of
a
PDV
histone
H4
gene
is
CpBV‐H4
[77].
When
transiently
expressed,
CpBV‐H4
has
been
found
to
significantly
impair
the
cellular
immune
response
as
well
as
suppress
host
H4
gene
expression
[77].
CpBV‐H4
is
very
similar
to
host
H4
but
posses
an
extend
N‐terminal
tail
[77].
The
removal
of
this
N‐terminal
tail
abolishes
the
inhibition
of
cellular
immunity
and
host
H4
gene
expression
mediated
by
CpBV‐H4
[77].
These
observations
have
lead
to
the
hypothesis
that
viral
H4
may
alter
chromatin
structure
through
epigenetic
modification,
resulting
in
altered
host
gene
expression
[77].
Evolution
of
Polydnavirus
Although
much
has
been
learned
about
the
lifecycle
and
genes
of
PDVs,
the
questions
of
where
they
originated
from
and
how
they
evolved
their
symbiotic
relationship
with
parasitic
wasps
have
remained
unanswered
[28].
There
has
been
two
main
viewpoints
on
the
evolution
of
PDVs;
either
they
are
the
descendents
of
pathogenic
insect
viruses
that
have
become
fixed
in
a
symbiotic
relationship
with
parasitoid
wasps
or
they
13
are
a
wasp
derived
genetic
secretion
system
[18,
73]
However,
these
two
theories
are
not
necessarily
mutually
exclusive
[73].
Host‐range
and
structural
similarities
between
PDVs
and
typical
‘free‐living’
viruses
of
their
lepidopteran
hosts
suggests
that
PDVs
evolved
from
insect
viruses
via
the
process
of
symbiogenesis
[16,20]
This
is
similar
in
theory
to
the
acquisition
of
mitochondria
and
chloroplasts
by
eukaryotic
cells
from
bacteria
[16,
20].
Evidence
supporting
this
hypothesis
has
recently
been
found
for
both
Bracoviruses
and
Ichnoviruses
[9,
10,
11].
Recently,
a
set
of
nudivirus
related
genes
that
are
expressed
in
the
ovaries
of
braconid
wasps
have
been
identified
[10].
Nudiviruses
are
a
diverse
group
of
large,
circular
dsDNA
viruses
that
are
pathogenic
for
a
wide
range
of
invertebrates
and
are
transmitted
via
feeding
and/or
mating
routes
[78].
Although
there
is
little
information
available
as
to
the
function
of
nudivirus
genes
they
do
share
a
set
of
essential
genes
with
another
well
characterized
insect
virus,
baculovirus
[10].
The
nudivirus
genes
found
to
be
expressed
in
the
female
wasp
that
are
conserved
in
baculoviruses
include
genes
that
encode
for
subunits
of
viral
RNA
polymerase,
proteins
involved
in
particle
assembly
and
packaging
as
well
as
envelope
proteins
[10].
However,
no
nudivirus
related
genes
could
be
found
packaged
in
viral
particles
[10].
A
similar
story
for
the
Ichnovirus
genera
is
also
emerging
[11].
Similarities
between
the
structural
proteins
of
Ichnovirus
and
typical
‘free‐
living’
insect
viruses,
ascoviruses,
have
been
discovered
which
suggests
that
these
PDVs
also
evolved
from
the
integration
of
an
insect
virus
[11].
Therefore
a
common
evolutionary
theory
can
be
drawn
up
for
both
families
of
PDVs
in
which
an
ancestral
virus
became
integrated
within
the
wasp
genome
70
to
100
million
years
ago
[10,
11].
Viral
genes
not
essential
for
parasitic
survival
in
the
lepidopteran
host
would
be
deleted
from
the
packaged
genome
over
time
and
replaced
with
wasp
genes
encoding
for
proteins
that
14
enhanced
parasitoid
survival
[11].
Although
the
exact
mechanism
of
this
evolution
has
not
been
discovered
as
of
yet,
it
is
clear
that
PDVs
and
parasitic
wasps
exemplify
a
novel
symbiosis
between
virus
and
host
and
represent
a
very
intriguing
and
expanding
field
of
study.
Endogenous
Retroviruses
Background
While
recent
findings
strongly
suggest
that
PDVs
evolved
from
typical
‘free‐living’
viruses
of
insects,
it
is
accepted
that
endogenous
retroviruses
(ERVs)
are
derived
from
their
exogenous
counterparts.
ERVs
are
the
remnants
of
exogenous
retroviruses
that
became
integrated
within
the
host
genome
in
germ
line
cells
and
were
subsequently
passed
down
vertically
within
a
species
in
a
classical
Mendelian
fashion
[57].
ERVs
have
been
found
to
be
present
in
all
vertebrate
genomes
[41].
The
continuous
infection
by
retroviruses
over
the
course
of
evolution
has
lead
to
the
accumulation
of
large
numbers
of
ERVs
within
the
genomes
of
mammals
and
other
vertebrates
[32].
This
is
evident
in
the
fact
that
ERVs
make
up
approximately
8
and
10
percent
of
the
human
and
murine
genomes,
respectively
[27,
48].
The
structure
of
the
typical
ERV
provirus
consists
of
the
main
retroviral
structural
genes
gag,
pro,
pol
and
env
which
are
flanked
on
both
sides
by
long
terminal
repeats
that
were
produced
during
reverse
transcription
[32].
Almost
all
retroviruses
that
have
become
endogenous
are
defective
due
to
the
accumulation
of
multiple
deletions,
mutations
and/or
stop
codons
and
are
therefore
no
longer
able
to
produce
infectious
virus
particles
[29].
However,
there
are
numerous
ERVs
that
still
contain
intact
open
reading
frames,
most
notably
in
the
env
gene,
and
thus
remain
to
be
15
expressed
[32].
In
addition
to
possible
roles
in
diseases,
such
as
cancer
and
autoimmune
disorders,
it
is
likely
that
many
ERVs
have
had
some
beneficial
effect
on
their
hosts
over
the
course
of
evolution
(14,
32,
41,).
This
is
evident
by
their
persistence
in
the
face
of
selective
pressures
that
would
remove
sequences
harmful
to
survival
of
the
host
(14,
32,
41,).
This
section
will
focus
on
the
beneficial
roles
ERVs
play
in
their
hosts,
such
as
interfering
with
exogenous
retroviruses
at
both
pre‐
and
post‐entry
stages
of
the
retroviral
lifecycle
(Figure2),
as
well
as
their
possible
roles
in
host
physiology.
Figure
2A:
Retroviral
lifecycle
and
blocks
imposed
by
endogenous
retrovirues.
The
initial
step
in
retroviral
infection,
the
binding
of
the
retrovirus
to
its
cellular
receptor
is
blocked
by
several
genes
derived
from
endogenous
retroviruses
(ERVs)
via
receptor
interference;
Fv­4
[40,
66,
67],
Rmcf
[34,70]
and
Rmcf2
[70]
found
in
mice;
enJSRV
env
of
sheep
[53,62];
ev3,
ev6
and
ev9
in
chickens
[60];
enFLV
env
in
domestic
cats
and
related
feline
species
[41];
HERV‐
16
W
env
derived
from
a
human
endogenous
retrovirus
protects
permissive
non‐
human
cells
in
cell
culture
suggesting
a
possible
protective
role
in
humans
[55]
.
Further
along
in
the
retroviral
lifecycle
the
FV­1
gene
found
in
mice
imposes
a
block
following
reverse
transcription
but
prior
to
nuclear
import
possibly
by
binding
to
the
viral
capsid,
preventing
disassembly
and
formation
of
the
pre‐
integration
complex
[1,
8,
75].
Two
transdominant
enJSRVs,
enJSRV561A
and
enJSRV‐20
are
capable
of
blocking
the
transport
of
JSRV
virus
particles
to
the
cell
surface
for
release
[2,
3,
49,
58,
53].
The
enJSRV
gag
protein
is
thought
to
bind
to
JSRV
gag,
disrupting
its
association
with
cellular
endosomal
transport
machinery
and
leading
to
its
subsequent
degradation
by
cellular
proteasomes
[2,
3,
49,
50,
43,
55].
Figure
adapted
from
reference
[63].
Receptor
Interference
The
block
in
entry
of
exogenous
retroviruses
by
ERV
components
is
one
of
the
main
symbiotic
effects
exhibited
by
ERVs
and
there
are
numerous
examples
of
this
protective
effect.
Endogenous
Jaagsiekte
sheep
retrovirus
(enJSRV)
has
been
shown
to
block
JSRV
entry
into
ovine
cells
[62].
Jaagsiekte
sheep
retrovirus
(JSRV)
is
an
oncogenic
betaretrovirus
that
is
the
causative
agent
of
ovine
adenocarcinoma,
a
transmissible
cancer
in
sheep
that
is
similar
to
human
bronchiole‐alveolar
carcinoma.
[13,
54].The
sheep
genome
contains
approximately
27
endogenous
Jaagsiekte
sheep
retrovirus
(enJSRV)
copies
[2].
Five
intact
proviruses,
enJSRV‐7,‐15,‐16,‐18
and
‐26,
contain
open
reading
frames
(ORFs)
for
all
the
retroviral
genes
and
share
85
to
89
percent
nucleotide
similarity
to
exogenous
JSRV
[53].
It
is
important
to
note
that
all
enJSRVs
lack
a
portion
of
the
env
gene
that
has
been
found
to
be
critical
for
transformation
in
vitro
[13].
In
regards
to
blocking
JSRV
entry,
the
exogenous
virus
is
observed
to
readily
infect
ovine
cells
which
have
no
enJSRV
expression
while
exhibiting
a
significantly
reduced
ability
to
enter
cells
that
express
high
levels
of
enJSRV
[53,
62].
This
impairment
in
infectivity
has
also
been
seen
in
cell
lines
that
were
transfected
with
and
stably
express
the
enJSRV
envelope
17
glycoprotein
[53,
62].
These
observations
suggest
that
the
mechanism
of
this
block
in
entry
may
be
through
receptor
interference
[52].
This
mechanism
of
resistance
to
JSRV
is
further
supported
by
the
fact
that
both
exogenous
JSRV
and
enJSRV
envelope
glycoprotein
bind
the
same
cellular
receptor,
hyaluronidase‐2
[62].
Receptor
interference
may
occur
through
either
enJSRV
env
saturating
the
cellular
receptor
or
by
limiting
its
surface
expression
[53].
In
either
case
this
results
in
the
reduced
accessibility
of
this
receptor
to
exogenous
JSRV
[53].
Figure
2B:
Receptor
interference
in
mice.
The
Fv­4,
Rmcf
and
Rmcf2
genes
are
derived
from
ecotropic,
polytropic
or
xenotropic
stains
of
MLV,
respectively,
and
encode
for
envelope
glycoproteins
[40,
34,
66,
67,
70].
These
Fv­4,
Rmcf
and
Rmcf2
encoded
glycoproteins
can
bind
the
CAT‐1,
Xpr1
or
Xpr1Sxv
receptors,
respectively.
It
is
believed
that
these
ERV
encoded
glycoproteins
associate
with
the
receptors
in
the
ER,
preventing
processing
and
transport
to
the
cell
surface.
18
This
results
in
an
entry
block
against
exogenous
ecotropic
strains
of
MLV
in
the
case
of
Fv­4
and
exogenous
polytropic
strains
of
MLV
in
the
case
of
Rmcf
and
Rmcf2.
There
are
also
three
genes,
Fv­4,
Rmcf
and
Rmcf2,
derived
from
ERVs,
found
in
the
genomes
of
mice
that
are
participate
in
receptor
interference
against
murine
gamma
retroviruses
[40
34,
70]
(Figure
2B).
The
Fv­4
gene
locus
has
been
found
to
provide
resistance
to
infection
caused
by
ecotropic
strains
of
murine
leukemia
virus
(MLV)
[40].
Ecotropic
strains
are
defined
as
MLVs
that
preferentially
replicate
in
murine
cells
[80].
The
Fv­4
locus
was
determined
to
be
a
defective
ERV
that
contains
the
3’
end
of
the
pol
gene
and
a
complete
env
gene
that
expresses
a
MLV
like
envelope
glycoprotein
[67].
The
Fv­4
env
gene
product
shares
approximately
70
percent
amino
acid
sequence
similarity
with
ecotropic
moloney
MLV
and
friend
MLV
[67].
This
Fv‐4
env
has
been
shown
to
be
capable
of
binding
the
ecotropic
MLV
receptor,
CAT‐1,
resulting
in
the
inhibition
of
entry
to
these
cells
by
MLV
via
receptor
interference
[67].
The
entry
block
is
not
absolute
and
depends
on
the
level
of
Fv‐4
expression
[67].
In
the
event
that
an
exogenous
virus
escapes
this
block
in
entry
and
infects
the
cell,
the
resulting
virus
particles
will
have
diminished
infectivity
[67].
This
is
due
to
incorporation
of
the
Fv­4
encoded
envelope
protein
that
contains
a
mutation
in
the
fusion
peptide
of
its
transmembrane
domain
that
is
required
for
entry
[67].
Found
in
the
genome
of
DBA/2J
mice,
the
Rmcf
gene
is
similar
to
the
Fv­4
gene
in
that
it
is
made
up
of
an
incomplete
pol
and
an
intact
env
gene
that
belongs
to
an
endogenous
polytropic
MLV
(P‐MLV)
[34].
Polytropic
MLVs
arise
in
mice
through
the
recombination
of
ecotropic
MLVs
with
endogenous
retroviral
envelope
genes
[81].
The
Rmcf
gene
product
interferes
with
exogenous
P‐MLV
entry
though
binding
of
Xpr1
receptor
that
P‐MLV
uses
for
entry
[34].
19
Another
mouse
gene
similar
to
Rmcf,
Rmcf­2,
is
also
capable
of
blocking
retroviral
entry
through
receptor
interference
[70].
Rmcf­2
also
blocks
P‐MLVs
but
is
composed
of
an
endogenous
xenotropic
MLV
(X‐MLV)
[70].
Xenotropic
MLVs
are
characterized
by
limited
replication
in
murine
cells
but
replicate
well
in
cells
from
other
species
[80].
This
endogenous
X‐MLV,
unlike
FV­4
and
Rmcf
does
not
contain
deletions
in
the
retroviral
genes
but
cannot
form
infectious
virus
due
to
a
stop
codon
in
the
integrase
gene
[70].
The
blocking
of
P‐MLVs
by
the
endogenous
X‐MLV
of
Rmcf2
can
only
occur
in
mice
with
the
Xpr1Sxv
receptor
variant,
found
in
many
wild
mouse
species,
that
permits
infections
by
both
P‐MLVs
and
X‐MLVs
[70].
These
three
murine
ERV
encoded
glycoproteins
are
believed
to
associate
with
their
receptors
in
the
endoplasmic
reticulum,
preventing
processing
and
transport
to
the
cell
surface
[63].
Resistance
to
exogenous
retroviral
infection
through
receptor
interference
by
ERVs
has
also
been
long
observed
in
chicken
and
cats
[32].
In
chickens,
three
defective
endogenous
avian
leukosis
viruses
(ALVs),
ev3,
ev6
and
ev9,
express
high
levels
of
ALV
subgroup
E
like
env
glycoproteins
[60].
Expression
of
these
glycoproteins
reduces
the
susceptibility
of
chickens
to
ALV
subgroup
E
infections
via
receptor
interference
[60].
In
domestic
cats
and
related
feline
species,
defective
endogenous
feline
leukaemia
virus
(FeLV)
related
sequences
are
found
in
8‐12
copies
per
cell
[46].
These
sequences
encode
for
a
truncated
env
gene
product
that
is
shed
from
the
cells
and
is
responsible
for
resistance
to
infection
by
FeLV
subgroup
B
through
a
receptor
interference
mechanism
[46].
20
Also
of
interest
in
terms
of
receptor
interference
is
a
human
endogenous
retrovirus
(HERV),
HERV‐W,
which
exists
in
an
estimated
30
to
100
copies
in
the
human
genome
[55].
HERV‐W
has
recently
been
show
to
induce
cellular
resistance
to
the
gamma
retrovirus
spleen
necrosis
virus
(SNV)
in
vitro
[55].
When
the
HERV‐W
env
gene
was
stably
expressed
in
a
canine
osteosarcoma
cell
line,
which
is
normally
permissive
for
SNV,
a
decrease
in
SNV
infection
up
to
10,000
fold
was
observed
compared
to
control
cell
lines
[51].
It
has
also
been
recently
shown
that
both
HERV‐W
env
and
SNV
bind
the
same
receptor,
RDR,
a
sodium‐dependent
neutral
amino
acid
transporter
[55].This
suggest
that
the
observed
resistance
is
due
to
receptor
interference
[55].
Although
the
biological
relevance
of
this
resistance
is
unclear
it
may
explain
the
resistance
of
human
cells
to
SNV
infection
despite
the
expression
of
RDR
in
many
human
tissues
[55].
Post­Entry
Blocks
In
addition
to
protecting
host
cells
from
retroviral
infection
by
blocking
viral
entry,
a
number
of
ERVs
are
also
capable
of
interfering
with
other
steps
of
the
retroviral
lifecycle
(Figure
2).
EnJSRVs,
in
addition
to
being
able
to
block
exogenous
virus
via
receptor
interference,
have
also
been
shown
to
block
exogenous
JSRV
at
a
later
stage
during
retroviral
infection
[49].
Two
enJSRVs,
enJSRV561A
and
enJSRV‐20,
have
been
shown
to
inhibit
virus
production
from
JSRV
infected
cells
[3].
These
ERVs
possess
intact
ORFs
for
all
viral
genes
(gag,
pro,
pol,
env)
except
for
orf‐x,
which
has
unknown
function,
due
to
the
presence
of
a
premature
stop
codon
[53].
This
transdominant
effect
of
these
two
enJSRVs
has
been
mapped
to
the
amino
acid
at
position
21
of
the
enJSRV
gag
polyprotein
[50].
In
21
exogenous
JSRV
and
all
other
beta
retroviruses
this
position
contains
a
conserved
arginine
(R21)
residue
however,
in
the
transdominant
enJSRV
this
position
is
occupied
by
a
tryptophan
residue
(W21)
[2,
50].
The
enJSRV56A1
gag
protein
is
able
to
interact
with
exogenous
JSRV
gag
protein
soon
after
synthesis
and
disrupt
its
pericentriolar
cellular
localization
[50].
Beta
retroviruses
such
as
JSRV
are
thought
to
assemble
in
the
pericentriolar
region
of
the
cytoplasm
and
utilize
the
cellular
endosomal
trafficking
machinery
in
order
to
transport
the
viral
particles
to
the
cellular
membrane
for
release
[3,
50]
This
is
unlike
other
retroviruses
that
assemble
at
the
cell
membrane
prior
to
release
as
is
observed
for
HIV
[50].
Although
the
precise
mechanism
of
this
transdominant
effect
is
not
known,
it
is
thought
that
JSRV
and
enJSRV
gag
co‐assemble,
resulting
in
the
disruption
of
the
interaction
between
JSRV
gag
and
the
endosomal
trafficking
machinery
[49,50]
This
is
expected
to
inhibit
viral
transport
to
the
cell
surface
[49,50].
The
enJSRV
gag
protein
is
thought
to
behave
like
a
misfolded
protein
due
to
the
tryptophan
residue
at
position
21,
which
is
hydrophobic
in
a
region
normally
exposed
in
JSRV
gag
[50].
This
leads
to
the
accumulation
of
chimeric
viral
particles
within
aggresomes
and
their
subsequent
degradation
by
the
cellular
proteasomes
[50].
It
is
of
interest
to
note
that
in
a
recent
study
an
enJSRV
which
likely
integrated
within
the
last
200
years,
enJSRV‐26,
was
found
to
escape
this
restriction
by
transdominant
enJSRV
when
expressed
in
a
transient
transfection
assay
[4].
This
finding
suggests
that
there
are
ongoing
counter‐adaptations
occurring
between
endogenous
and
exogenous
JSRV
[4].
In
this
relationship
enJSRVs
that
protect
against
JSRV
are
positively
selected
for
and
that
JSRV
can
evolve
mechanisms
to
evade
this
resistance
[4].
22
ERV
mediated
resistance
to
retroviral
infection
due
to
post‐entry
blocks
in
the
retroviral
lifecycle
are
also
seen
in
mice
(Figure
2).
The
Fv1
gene
has
been
found
to
provide
resistance
against
ecotropic
strains
of
MLV
[8,
75].
Although
this
restriction
is
not
absolute
it
has
been
observed
to
reduce
viral
titers
by
50
to
1000
fold
in
vitro
[8,
75].
The
Fv1
gene
is
derived
from
the
gag
region
of
the
MuERV‐L
family
of
endogenous
retroviruses,
a
family
of
ERVs
that
is
unrelated
to
MLV,
and
encodes
a
retroviral
capsid‐like
protein
[8,
75].
There
are
two
main
alleles
of
FV­1,
Fv1n
and
Fv1b
that
facilitate
the
division
of
ecotropic
MLVs
into
N‐tropic
and
B‐tropic
viruses
[65,
82].
The
Fv1n
allele,
found
in
NIH
Swiss
mice,
provides
resistance
to
B‐tropic
MLVs
but
remains
susceptible
to
N‐tropic
MLVs
[83].
This
is
in
contrast
to
the
Fv1b
allele,
found
in
BALB/c
mice,
which
shows
the
reciprocal
pattern
of
resistance/susceptibility
[1,
83].
A
third
allele,
Fv1nr,
restricts
B‐tropic
MLVs
and
some,
but
not
all,
N‐tropic
MLVs
[83].
Fv1nr
is
found
in
various
inbred
strains
of
mice
and
possibly
some
wild
mice
[83].
N‐tropic
MLVs
that
are
restricted
by
Fv1nr
are
referred
to
as
NR‐tropic
[83].
A
fourth
allele
of
FV1,
Fv1null
allele
does
not
provide
resistance
to
any
subgroup
of
MLVs
[1].
Although
the
mechanism
of
this
resistance
remains
to
be
determined
it
has
been
deduced
that
the
Fv1
gene
product
targets
the
viral
capsid
protein
to
block
the
retroviral
lifecycle
after
reverse
transcription
of
the
viral
genome
but
prior
to
nuclear
import
and
integration
[75].
One
possible
mechanism
is
that
the
Fv1
encoded
capsid‐like
proteins
interact
with
the
exogenous
virus
capsid,
interfering
with
capsid
disassembly
and
formation
of
the
pre‐integration
complex
thus
preventing
integration
and
virus
production
[75].
23
Roles
in
Host
Physiology
ERVs,
in
addition
to
interfering
with
exogenous
retrovirus
infection
may
also
play
essential
roles
in
host
physiology.
In
humans,
two
ERV
env
proteins
Syncytin‐1
and
Syncytin‐2
which
are
derived
from
HERV‐W
and
HERV‐FRD,
respectively
have
been
implicated
in
the
process
of
placenta
morphogenesis
[21].
The
placenta
is
a
complex
structure
that
permits
diffusion
between
fetal
and
maternal
circulatory
systems
[45].
During
the
development
of
the
placenta,
a
crucial
process
involves
the
differentiation
and
fusion
of
fetal
trophoblast
cells
which
results
in
the
formation
of
the
syncytial
trophoblast
[45]
This
multinucleated
layer
erodes
a
path
in
the
uterine
epithelium
during
implantation
[45].
The
syncytial
trophoblast
layer
makes
up
the
boundary
between
fetal
and
maternal
compartments
of
the
placenta
[42].
The
molecular
mechanisms
involved
in
this
process
are
not
that
well
understood,
however,
a
role
for
syncytin‐1
and
syncytin‐2
in
this
process
is
suggested
[42].
This
is
supported
by
the
fact
that
the
two
syncytins
have
been
shown
to
be
fusogenic,
able
to
induce
cell‐cell
fusion,
ex
vivo
and
are
specifically
expressed
at
the
trophoblast‐syncytial
trophoblast
interface
within
the
placenta
[42].
Additionally,
the
receptors
for
syncytin‐1
and
syncytin‐2,
RDR,
an
amino
acid
transporter
and
major
facilitator
superfamily
domain
containing
2,
a
presumptive
carbohydrate
transporter,
are
expressed
at
relatively
high
levels
in
the
placenta
[21].
The
role
of
the
syncytins
in
human
placenta
morphogenesis
requires
more
intense
study
but
it
is
appears
that
these
ERV
proteins
are
involved
and
may
be
essential
to
this
process.
Two
ERV
env
genes
that
behave
in
a
similar
fashion
to
human
syncytin‐1
and
syncytin‐2,
but
are
phylogenetically
unrelated,
have
been
identified
in
the
murine
genome,
syncytin‐A
and
syncytin‐B
[19].
Much
like
the
24
human
syncytins,
the
murine
syncytins
have
been
shown
to
be
specifically
expressed
in
the
placenta
within
the
syncytial
trophoblast
and
are
highly
fusogenic
in
vitro
[19]
Another
role
of
ERV
env
proteins
in
host
physiology
is
suggested
by
the
fact
that
many
exogenous
retroviral
envelope
proteins
can
suppress
host
immune
responses
[37].
This
is
due
to
the
presence
of
a
highly
conserved
immunosuppressive
domain
[37].
Recently,
it
has
been
demonstrated
that
in
both
human
and
mice
one
of
the
syncytin
proteins,
syncitin‐2
in
humans
and
syncytin‐B
in
mice,
possess
immunosuppressive
properties
[42].
This
was
demonstrated
by
the
ability
of
injected
syncytin
expressing
tumor
cells
to
develop
into
large
tumors
that
persisted
in
immunocompetent
allogeneic
mice
[42].
In
contrast
these
mice
cleared
such
tumors
in
the
absence
of
syncytin
expression
in
an
immune
mediated
fashion
[42].
Other
HERVs
displaying
this
same
immunosuppressive
effect
include
HERV‐H
and
ERV‐3
[32,
37].
While
this
suggests
that
ERVs
may
play
a
role
in
cancer
progression
and
persistence
it
also
raises
the
idea
that
immunosuppressive
ERV
proteins
expressed
in
the
placenta
may
have
beneficial
effects
[32,
37].
ERV
mediated
immunosuppression
could
play
a
key
role
in
protecting
the
developing
fetus
from
attack
by
the
maternal
immune
system,
thus
preventing
rejection
of
the
developing
fetus
[32,
37].
Supporting
the
theory
that
syncytins
are
important
in
placenta
development
in
humans
and
mice,
it
has
been
shown
that
enJSRVs
env
expression
is
essential
to
placenta
morphogenesis
in
sheep
[17].
EnJSRVs
are
highly
expressed
in
the
female
reproductive
tract
with
expression
concentrated
in
the
trophoblast
giant
binucleate
cells
and
multinucleated
syncytia
[17].
These
structures
form
from
the
fusion
of
trophoblast
cells
and
make
up
the
placentomes,
which
are
analogous
to
the
placenta
in
humans
[17].
The
25
receptor
for
the
enJSRV
envelope
glycoprotein,
HYAL2,
is
also
highly
expressed
in
these
tissues,
suggesting
a
fusogenic
role
in
placenta
morphogenesis
as
proposed
for
the
syncytins.
[2]
In
a
2006
study
by
Spencer
et
al.
expression
of
enJSRV
env
mRNAs
in
the
reproductive
tract
of
pregnant
sheep
was
inhibited
by
use
of
morpholino
antisense
oligonucleotides
(MAO)
to
study
the
biological
relevance
of
this
enJSRV
expression
[17].
The
injection
of
enJSRV
env
specific
MAO
resulted
in
the
development
of
fetuses
that
were
fragile,
smaller
and
contained
fewer
trophoblast
giant
binucleate
cells
compared
to
control
animals
[17].
This
disruption
in
conceptus
formation
was
then
followed
by
pregnancy
loss
in
nearly
all
of
the
sheep
that
received
enJSRV
env
MAOs
[17].
This
study
proved
that
enJSRV
has
an
essential
biological
role
in
placenta
morphogenesis
and
the
establishment
of
pregnancy
in
sheep.
In
addition,
this
discovery
has
added
to
the
body
of
evidence
that
suggests
ERVs
may
play
essential
roles
in
placenta
formation
and
perhaps
other
physiological
processes
in
other
vertebrates.
Other
symbiotic
viruses
In
addition
to
PDVs
and
ERVs
there
are
also
a
number
of
other
viruses
that
have
been
found
to
have
a
beneficial
effect
on
their
hosts.
A
recent
study
by
Barton
et
al.
has
raised
the
issue
as
to
whether
latent
herpes
virus
infections
may
have
a
symbiotic
effect
by
modulating
the
host’s
innate
immune
system
[6].
This
immune
modulation
may
help
protect
the
host
from
potentially
life
threatening
infections
[6].
In
this
study
mice
latently
infected
with
gamma
herpes
68,
which
is
genetically
similar
to
Epstein‐Barr
virus,
or
murine
cytomegalovirus,
which
is
similar
to
human
cytomegalovirus,
were
challenged
with
26
Listeria
monocytogenes
and
Yersinia
pestis,
the
causative
agent
of
the
plague
[6].
In
both
cases
latently
infect
mice
exhibited
a
significant
reduction
in
bacterial
replication
and
systemic
spread
as
compared
to
control
mice
without
a
latent
herpes
infection
[6].
This
protection
was
correlated
with
higher
levels
of
serum
IFN‐γ
and
TNF‐α
as
well
as
higher
levels
of
macrophage
activation
present
in
latently
infected
mice
[6].
However,
this
protective
effect
did
not
apply
to
all
pathogens
as
West
Nile
virus
infection
preceded
the
same
in
the
presence
or
absence
of
latent
herpes
infection
[6].
The
authors
propose
a
cross‐
protective
mechanism
in
which
latent
viral
infection
results
in
the
chronic
presentation
of
small
amounts
of
viral
antigens
during
reactivation
[6].
This
results
in
chronic
T‐cell
activation
and
IFN‐y
secretion
that
protects
the
host
from
other
pathogens
by
activating
the
innate
immune
system,
particularly
macrophages
[6].
This
issue
has
not
been
studied
in
humans
but
due
to
the
genetic
similarity
between
these
pathogens
of
mice
and
those
of
humans
it
is
plausible
that
herpes
viruses
may
also
have
a
similar
beneficial
role
in
humans
[6].
However,
in
a
follow
up
study
by
Blackman
et
al.
it
was
found
that
this
symbiotic
protective
effect
failed
to
persist
with
life
long
viral
latency
in
infected
mice
[79].
Protection
from
bacterial
infections
was
found
to
be
transit,
lasting
as
long
as
5
months
while
the
elevated
serum
levels
of
IFN‐γ
and
TNF‐α
were
undetectable
after
2
months
[79].
Another
study
that
suggests
a
role
for
herpes
virus
in
the
modulation
of
the
immune
system
investigated
wheatear
the
infectious
burden
of
children
was
associated
with
IgE
sensitization
to
environmental
antigens
[52].
In
this
study
the
authors
identified
EBV
and
CMV
infection
as
playing
a
role
in
the
level
of
IgE
sensitization
[52].
It
was
found
that
the
risk
of
IgE
sensitization
was
reduced
in
children
that
were
infected
with
EBV
by
age
two
and
this
effect
was
increased
with
cytomegalovirus
co‐infection
[52].
These
studies
27
strongly
suggest
a
role
of
herpes
viruses
in
shaping
the
immune
response,
both
in
terms
of
pathogen
resistance
and
the
development
of
allergies.
These
observations
also
raise
the
question
as
to
whether
other
common
viral
infections
may
have
beneficial
immune
modulating
effects.
Symbiotic
viruses
are
also
seen
in
fugal‐plant
associations
where
the
interaction
can
become
very
complex.
An
interesting
example
is
seen
in
the
symbiotic
relationship
between
the
tropical
panic
grass,
Dichanthelium
lanuginosum
and
the
fungus
Curvularia
protuberate
[44].
Studies
have
shown
that
when
associated
with
the
fungus,
the
plant
can
grow
in
soil
temperatures
up
to
65°C
whereas
non‐fungus
associated
plants
cannot
grow
at
temps
above
38°C
[44].
This
heat‐resistance
effect
was
found
to
be
dependent
on
the
presence
of
a
RNA
virus
found
within
the
fungus
referred
to
as
CThTV
[44].
It
was
proposed
that
the
virus
interferes
with
the
induction
of
the
stress
response
pathway
in
the
plants
resulting
in
a
decrease
in
the
production
of
reactive
oxygen
species
that
are
potentially
damaging
to
the
plant
[44].
Concluding
Remarks
As
this
review
has
demonstrated
not
all
eukaryotic
viruses
have
detrimental
or
benign
effects
on
the
hosts
they
infect
but
in
fact
there
are
numerous
examples
of
viral
infections
that
have
beneficial
effects
on
their
hosts.
Two
main
themes
as
to
how
these
symbiotic
viruses
benefit
their
hosts
have
emerged
in
this
review;
the
first
being
a
result
of
lateral
gene
transfer
via
integration
and
secondly
though
modulation
of
the
immune
system.
In
the
case
of
lateral
gene
transfer,
it
has
been
shown
that
a
number
of
ERVs
have
provided
28
their
hosts
with
new
genetic
material
that
is
capable
of
being
expressed.
Some
of
these
ERV
derived
proteins
are
able
to
protect
against
retroviral
infection
and
others
may
play
essential
roles
in
host
physiology.
Also
following
this
theme,
ancestral
PDVs
that
infected
parasitic
wasps
millions
of
years
ago
have
provided
these
wasps
with
the
ability
to
package
and
transfer
immunosuppressive
genes
that
ensure
the
survival
and
development
of
their
offspring
within
a
lepidopteran
host.
The
process
of
acquiring
new
functions
through
a
symbiotic
relationship
with
a
virus
is
comparable
to
the
endosymbiotic
theory
that
describes
the
acquisition
of
the
chloroplast
and
mitochondria
by
the
ancestral
eukaryotic
cells
from
bacteria
[23].
These
discoveries
suggest
that
it
is
likely
that
other
components
of
host
physiology
within
many
species
have
been
acquired
though
the
process
of
symbiotic
relationships
with
viruses.
Support
for
this
comes
from
the
fact
that
the
genomes
of
many
species
are
composed
of
large
amount
of
ERV
sequences.
This
introduced
genetic
material
has
the
potential
to
encode
for
functions
that
would
take
millions
of
years
longer
to
develop
though
simple
Darwinian
evolution
allowing
for
more
rapid
evolution
[43]
This
theory
was
popularized
by
Lynn
Margulis
who
suggested
that
symbiotic
relationship
are
the
driving
force
of
evolution
[43]
.
The
second
theme,
immune
modulation,
suggests
that
numerous
viral
infections
may
play
important
roles
in
shaping
the
immune
responses
of
their
hosts.
Viral
mediated
immune
modulation
may
protect
the
host
against
potentially
life
threatening
illness
and
in
turn
increase
the
chance
of
survival.
This
was
seen
in
the
studies
that
showed
an
apparent
role
of
latent
herpes
viruses
in
protecting
their
hosts
from
infection
by
L.
monocytogenes
and
Y.
pestis
Listeria
through
a
heightened
state
of
innate
immune
activation,
as
well
as
the
possible
role
of
EBV
modulating
the
development
of
allergies
[6,
52].
This
effect
has
also
been
observed
in
plants
in
which
a
fungal
virus
29
appears
to
prevent
damage
to
the
plant
in
response
to
high
temperatures
through
a
reduction
in
a
potentially
destructive
stress
response
[44].
From
this
review
it
is
apparent
that
viruses
are
capable
of
more
than
they
are
generally
given
credit
for.
With
roles
in
pathogen
resistance,
immune
modulation
and
host
physiology,
viruses
have
potentially
played
an
important
role
in
the
evolution
of
eukaryotic
life.
The
symbiotic
virus
host
relationships
discovered
so
far
are
likely
just
the
tip
of
the
ice
berg
and
represent
an
intriguing
and
expanding
area
of
virology.
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