Viruses,
Journal Year:
2024,
Volume and Issue:
16(9), P. 1423 - 1423
Published: Sept. 6, 2024
HIV-1
virion
maturation
is
an
essential
step
in
the
viral
replication
cycle
to
produce
infectious
virus
particles.
Gag
and
Gag-Pol
polyproteins
are
assembled
at
plasma
membrane
of
virus-producer
cells
bud
from
it
extracellular
compartment.
The
newly
released
progeny
virions
initially
immature
noninfectious.
However,
once
polyprotein
cleaved
by
protease
virions,
mature
capsid
proteins
assemble
form
fullerene
core.
This
core,
harboring
two
copies
genomic
RNA,
transforms
morphology
into
morphological
transformation
referred
as
maturation.
Virion
influences
distribution
Env
glycoprotein
on
surface
induces
conformational
changes
necessary
for
subsequent
interaction
with
CD4
receptor.
Several
host
factors,
including
like
cyclophilin
A,
metabolites
such
IP6,
lipid
rafts
containing
sphingomyelins,
have
been
demonstrated
influence
review
article
delves
processes
recruitment,
emphasis
role
cell
factors
environmental
conditions.
Additionally,
we
discuss
microscopic
technologies
assessing
development
current
antivirals
specifically
targeting
this
critical
replication,
offering
long-acting
therapeutic
options.
The
HIV-1
capsid
has
emerged
as
a
tractable
target
for
antiretroviral
therapy.
Lenacapavir,
developed
by
Gilead
Sciences,
is
the
first
capsid-targeting
drug
approved
medical
use.
Here,
we
investigate
effect
of
lenacapavir
on
HIV
stability
and
uncoating.
We
employ
single
particle
approach
that
simultaneously
measures
content
release
lattice
persistence.
demonstrate
lenacapavir's
potent
antiviral
activity
predominantly
due
to
lethal
hyperstabilisation
resultant
loss
compartmentalisation.
This
study
highlights
disrupting
metastability
powerful
strategy
development
novel
antivirals.
Science Advances,
Journal Year:
2023,
Volume and Issue:
9(1)
Published: Jan. 6, 2023
The
maturation
of
HIV-1
capsid
protein
(CA)
into
a
cone-shaped
lattice
is
critical
for
viral
infectivity.
CA
can
self-assemble
range
morphologies
made
~175
to
250
hexamers
and
12
pentamers.
cellular
polyanion
inositol
hexakisphosphate
(IP6)
has
recently
been
demonstrated
facilitate
conical
formation
by
coordinating
ring
arginine
residues
within
the
central
cavity
However,
kinetic
interplay
events
during
IP6
coassembly
unclear.
In
this
work,
we
use
coarse-grained
molecular
dynamics
simulations
elucidate
mechanism
formation,
including
role
played
IP6.
We
show
that
IP6,
in
small
quantities
at
first,
promotes
curvature
generation
trapping
pentameric
defects
growing
shifts
assembly
behavior
toward
kinetically
favored
outcomes.
Our
analysis
also
suggests
stabilize
metastable
intermediates
induce
structural
pleomorphism
mature
capsids.
Proceedings of the National Academy of Sciences,
Journal Year:
2023,
Volume and Issue:
120(13)
Published: March 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.
Proceedings of the National Academy of Sciences,
Journal Year:
2023,
Volume and Issue:
120(18)
Published: April 24, 2023
The
HIV-1
capsid
houses
the
viral
genome
and
interacts
extensively
with
host
cell
proteins
throughout
life
cycle.
It
is
composed
of
protein
(CA),
which
assembles
into
a
conical
fullerene
lattice
roughly
200
CA
hexamers
12
pentamers.
Previous
structural
analyses
individual
pentamers
have
provided
valuable
insight
structure
function,
but
detailed
information
about
these
assemblies
in
broader
context
lacking.
In
this
study,
we
combined
cryoelectron
tomography
single
particle
analysis
(SPA)
microscopy
to
determine
structures
continuous
regions
containing
both
We
also
developed
method
liposome
scaffold-based
vitro
assembly
("lattice
templating")
that
enabled
us
directly
study
under
wider
range
conditions
than
has
previously
been
possible.
Using
approach,
identified
critical
role
for
inositol
hexakisphosphate
pentamer
formation
determined
bound
capsid-targeting
antiretroviral
drug
GS-6207
(lenacapavir).
Our
work
reveals
key
details
mature
establishes
combination
templating
SPA
as
robust
strategy
studying
retroviral
interactions
antiviral
compounds.
Microbiology and Molecular Biology Reviews,
Journal Year:
2023,
Volume and Issue:
87(4)
Published: Sept. 26, 2023
The
HIV-1
capsid,
composed
of
approximately
1,200
copies
the
capsid
protein,
encases
genomic
RNA
alongside
viral
nucleocapsid,
reverse
transcriptase,
and
integrase
proteins.
After
cell
entry,
interacts
with
a
myriad
host
factors
to
traverse
cytoplasm,
pass
through
nuclear
pore
complex
(NPC),
then
traffic
chromosomal
sites
for
DNA
integration.
Integration
may
very
well
require
dissolution
but
where
when
this
uncoating
event
occurs
remains
hotly
debated.
Based
on
size
constraints,
long-prevailing
view
was
that
preceded
transport,
recent
research
has
indicated
remain
largely
intact
during
import,
perhaps
some
structural
remodeling
required
NPC
traversal.
Completion
transcription
in
nucleus
further
aid
uncoating.
One
canonical
type
factor,
typified
by
CPSF6,
leverages
Phe-Gly
(FG)
motif
bind
capsid.
Recent
shown
these
peptides
reside
amid
prion-like
domains
(PrLDs),
which
are
stretches
protein
sequence
devoid
charged
residues.
Intermolecular
PrLD
interactions
along
exterior
shell
impart
avid
factor
binding
productive
infection.
Herein
we
overview
capsid-host
implicated
ingress
discuss
important
questions
moving
forward.
Highlighting
clinical
relevance,
long-acting
ultrapotent
inhibitor
lenacapavir,
engages
same
pocket
as
FG
factors,
recently
approved
treat
people
living
HIV.
ACS Nano,
Journal Year:
2024,
Volume and Issue:
18(4), P. 2928 - 2947
Published: Jan. 19, 2024
The
HIV-1
core
consists
of
a
cone-shaped
capsid
shell
made
protein
(CA)
hexamers
and
pentamers
encapsulating
the
viral
genome.
disassembly,
referred
to
as
uncoating,
is
important
for
productive
infection;
however,
location,
timing,
regulation
uncoating
remain
controversial.
Here,
we
employ
amber
codon
suppression
directly
label
CA.
In
addition,
fluid
phase
fluorescent
probe
incorporated
into
detect
small
defects
in
lattice.
This
double-labeling
strategy
enables
visualization
single
cores
vitro
living
cells,
which
found
always
proceed
through
at
least
two
distinct
steps─the
formation
defect
lattice
that
initiates
gradual
loss
CA
below
detectable
level.
Importantly,
intact
containing
markers
enter
uncoat
nucleus,
evidenced
by
sequential
both
markers,
prior
establishing
infection.
two-step
process
observed
different
including
macrophage
line.
Notably,
lag
between
release
marker
terminal
appears
be
independent
cell
type
or
reverse
transcription
much
longer
(>5-fold)
nuclear
capsids
compared
cell-free
cytosol,
suggesting
stabilized
capsid-binding
factors.
Our
results
imply
nucleus
initiated
localized
global
EMBO Reports,
Journal Year:
2023,
Volume and Issue:
24(5)
Published: March 27, 2023
Abstract
HIV‐1
uses
inositol
hexakisphosphate
(IP6)
to
build
a
metastable
capsid
capable
of
delivering
its
genome
into
the
host
nucleus.
Here,
we
show
that
viruses
are
unable
package
IP6
lack
protection
and
detected
by
innate
immunity,
resulting
in
activation
an
antiviral
state
inhibits
infection.
Disrupting
enrichment
results
defective
capsids
trigger
cytokine
chemokine
responses
during
infection
both
primary
macrophages
T‐cell
lines.
Restoring
with
single
mutation
rescues
ability
infect
cells
without
being
detected.
Using
combination
mutants
CRISPR‐derived
knockout
cell
lines
for
RNA
DNA
sensors,
immune
sensing
is
dependent
upon
cGAS–STING
axis
independent
detection.
Sensing
requires
synthesis
viral
prevented
reverse
transcriptase
inhibitors
or
active‐site
mutation.
These
demonstrate
required
can
successfully
transit
avoid
sensing.