Cell Reports,
Год журнала:
2024,
Номер
43(3), С. 113941 - 113941
Опубликована: Март 1, 2024
Resting
CD4
T
cells
resist
productive
HIV-1
infection.
The
HIV-2/simian
immunodeficiency
virus
protein
viral
accessory
X
(Vpx)
renders
these
permissive
to
infection,
presumably
by
alleviating
blocks
at
cytoplasmic
reverse
transcription
and
subsequent
nuclear
import
of
reverse-transcription/pre-integration
complexes
(RTC/PICs).
Here,
spatial
analyses
using
quantitative
imaging
techniques
reveal
that
capsids
containing
RTC/PICs
are
readily
imported
into
the
nucleus,
recruit
host
dependency
factor
CPSF6,
translocate
speckles
in
resting
cells.
Reverse
transcription,
however,
remains
incomplete,
impeding
proviral
integration
gene
expression.
Vpx
or
pharmacological
inhibition
deoxynucleotide
triphosphohydrolase
(dNTPase)
activity
restriction
SAM
domain
HD
domain-containing
1
(SAMHD1)
increases
levels
reverse-transcribed
cDNA
facilitates
integration.
Nuclear
intranuclear
transport
therefore
do
not
pose
important
cells,
limitation
SAMHD1's
dNTPase
constitutes
main
pre-integration
block
Abstract
HIV
can
infect
non-dividing
cells
because
the
viral
capsid
overcome
selective
barrier
of
nuclear
pore
complex
and
deliver
genome
directly
into
nucleus
1,2
.
Remarkably,
intact
is
more
than
1,000
times
larger
size
limit
prescribed
by
diffusion
3
This
in
central
channel
composed
intrinsically
disordered
nucleoporin
domains
enriched
phenylalanine–glycine
(FG)
dipeptides.
Through
multivalent
FG
interactions,
cellular
karyopherins
their
bound
cargoes
solubilize
this
phase
to
drive
nucleocytoplasmic
transport
4
By
performing
an
vitro
dissection
complex,
we
show
that
a
pocket
on
surface
similarly
interacts
with
motifs
from
multiple
nucleoporins
interaction
licences
capsids
penetrate
FG-nucleoporin
condensates.
karyopherin
mimicry
model
addresses
key
conceptual
challenge
for
role
entry
offers
explanation
as
how
exogenous
entity
much
any
known
cargo
may
be
able
non-destructively
breach
envelope.
Nature,
Год журнала:
2024,
Номер
626(8000), С. 843 - 851
Опубликована: Янв. 24, 2024
Abstract
HIV-1
infection
requires
nuclear
entry
of
the
viral
genome.
Previous
evidence
suggests
that
this
proceeds
through
pore
complexes
(NPCs),
with
120
×
60
nm
capsid
squeezing
an
approximately
60-nm-wide
central
channel
1
and
crossing
permeability
barrier
NPC.
This
can
be
described
as
FG
phase
2
is
assembled
from
cohesively
interacting
phenylalanine–glycine
(FG)
repeats
3
selectively
permeable
to
cargo
captured
by
transport
receptors
(NTRs).
Here
we
show
assemblies
target
NPCs
efficiently
in
NTR-independent
manner
bind
directly
several
types
repeats,
including
barrier-forming
cohesive
repeats.
Like
NTRs,
readily
partitions
into
vitro
serve
NPC
mimic
excludes
much
smaller
inert
probes
such
mCherry.
Indeed,
protein
greatly
enhanced
assembly,
which
also
allows
encapsulated
clients
enter.
Thus,
our
data
indicate
behaves
like
NTR,
its
interior
serving
a
container.
Because
capsid-coating
trans
-acting
NTRs
would
increase
diameter
10
or
more,
suggest
‘self-translocating’
undermines
size
restrictions
imposed
scaffold,
thereby
bypassing
otherwise
effective
infection.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(4)
Опубликована: Янв. 19, 2024
Nuclear
import
and
uncoating
of
the
viral
capsid
are
critical
steps
in
HIV-1
life
cycle
that
serve
to
transport
release
genomic
material
into
nucleus.
Viral
core
involves
translocating
at
nuclear
pore
complex
(NPC).
Notably,
central
channel
NPC
appears
often
accommodate
allow
passage
intact
capsid,
though
mechanistic
details
process
remain
be
fully
understood.
Here,
we
investigate
molecular
interactions
operate
concert
between
regulate
translocation
through
channel.
To
this
end,
develop
a
“bottom-up”
coarse-grained
(CG)
model
human
from
recently
released
cryo-electron
tomography
structure
then
construct
composite
membrane-embedded
CG
models.
We
find
successful
cytoplasmic
side
is
contingent
on
compatibility
morphology
dimension
proper
orientation
approach
side.
The
dynamics
driven
by
maximizing
contacts
phenylalanine-glycine
nucleoporins
capsid.
For
docked
capsids,
structural
analysis
reveals
correlated
striated
patterns
lattice
disorder
likely
related
intrinsic
elasticity.
Uncondensed
inside
augments
overall
Our
results
suggest
“elasticity”
can
also
aid
adapt
stress
structurally
during
translocation.
Annual Review of Virology,
Год журнала:
2022,
Номер
9(1), С. 261 - 284
Опубликована: Июнь 15, 2022
After
cell
entry,
human
immunodeficiency
virus
type
1
(HIV-1)
replication
involves
reverse
transcription
of
the
RNA
genome,
nuclear
import
subviral
complex
without
envelope
breakdown,
and
integration
viral
complementary
DNA
into
host
genome.
Here,
we
discuss
recent
evidence
indicating
that
completion
genome
uncoating
occur
in
nucleus
rather
than
cytoplasm,
as
previously
thought,
suggest
a
testable
model
for
uncoating.
Multiple
studies
indicated
cone-shaped
capsid,
which
encases
proteins,
not
only
serves
reaction
container
shield
from
innate
immune
sensors
but
also
may
constitute
elusive
HIV-1
factor.
Rupture
capsid
be
triggered
by
transcription,
yet-unknown
factors,
or
physical
damage,
it
appears
to
close
temporal
spatial
association
with
process.
Nature Microbiology,
Год журнала:
2022,
Номер
7(11), С. 1762 - 1776
Опубликована: Окт. 26, 2022
Abstract
Of
the
13
known
independent
zoonoses
of
simian
immunodeficiency
viruses
to
humans,
only
one,
leading
human
virus
(HIV)
type
1(M)
has
become
pandemic,
causing
over
80
million
infections.
To
understand
specific
features
associated
with
pandemic
human-to-human
HIV
spread,
we
compared
replication
HIV-1(M)
non-pandemic
HIV-(O)
and
HIV-2
strains
in
myeloid
cell
models.
We
found
that
lineages
replicate
less
well
than
owing
activation
cGAS
TRIM5-mediated
antiviral
responses.
applied
phylogenetic
X-ray
crystallography
structural
analyses
identify
differences
between
capsids.
genetic
reversal
two
amino
acid
adaptations
enables
TRIM5,
innate
immune
propose
a
model
which
parental
lineage
evolved
capsid
prevents
TRIM5
triggering,
thereby
allowing
silent
cells.
hypothesize
this
adaptation
promotes
spread
through
avoidance
response
activation.
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Окт. 6, 2022
Abstract
Cellular
proteins
CPSF6,
NUP153
and
SEC24C
play
crucial
roles
in
HIV-1
infection.
While
weak
interactions
of
short
phenylalanine-glycine
(FG)
containing
peptides
with
isolated
capsid
hexamers
have
been
characterized,
how
these
cellular
factors
functionally
engage
biologically
relevant
mature
lattices
is
unknown.
Here
we
show
that
prion-like
low
complexity
regions
(LCRs)
enable
avid
binding
to
lattices.
Structural
studies
revealed
multivalent
CPSF6
assembly
mediated
by
LCR-LCR
interactions,
which
are
templated
FG
a
subset
hydrophobic
pockets
positioned
along
adjoining
hexamers.
In
infected
cells,
LCR-mediated
cores
essential
for
functional
virus-host
interactions.
The
investigational
drug
lenacapavir
accesses
unoccupied
the
complex
potently
impair
inside
nucleus
without
displacing
tightly
bound
cofactor
from
virus
cores.
These
results
establish
previously
undescribed
mechanisms
antiviral
action.
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(13)
Опубликована: Март 21, 2023
Increasing
evidence
has
suggested
that
the
HIV-1
capsid
enters
nucleus
in
a
largely
assembled,
intact
form.
However,
not
much
is
known
about
how
cone-shaped
interacts
with
nucleoporins
(NUPs)
nuclear
pore
for
crossing
complex.
Here,
we
elucidate
NUP153
binds
by
engaging
assembled
protein
(CA)
lattice.
A
bipartite
motif
containing
both
canonical
and
noncanonical
interaction
modules
was
identified
at
C-terminal
tail
region
of
NUP153.
The
cargo-targeting
phenylalanine-glycine
(FG)
engaged
CA
hexamer.
By
contrast,
previously
unidentified
triple-arginine
(RRR)
targeted
tri-hexamer
interface
capsid.
infection
studies
indicated
FG-
RRR-motifs
were
important
import
cores.
Moreover,
presence
stabilized
tubular
assemblies
vitro.
Our
results
provide
molecular-level
mechanistic
contributes
to
entry
into
nucleus.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Июнь 24, 2023
Abstract
The
movement
of
viruses
and
other
large
macromolecular
cargo
through
nuclear
pore
complexes
(NPCs)
is
poorly
understood.
human
immunodeficiency
virus
type
1
(HIV-1)
provides
an
attractive
model
to
interrogate
this
process.
HIV-1
capsid
(CA),
the
chief
structural
component
viral
core,
a
critical
determinant
in
transport
virus.
interactions
with
NPCs
are
dependent
on
CA,
which
makes
direct
contact
nucleoporins
(Nups).
Here
we
identify
Nup35,
Nup153,
POM121
coordinately
support
entry.
For
Nup35
POM121,
dependence
was
cyclophilin
A
(CypA)
interaction
CA.
Mutation
CA
or
removal
soluble
host
factors
changed
NPC.
make
via
regions
containing
phenylalanine
glycine
motifs
(FG-motifs).
Collectively,
these
findings
provide
additional
evidence
that
core
functions
as
receptor
(NTR)
exploits
modulate
NPC
requirements
during
invasion.