regulation of hiv transcription and mechanisims of latency. viral – host interactions
DESCRIPTION
Lost in transcription – mechanisms that drive HIV latency. Ongoing Projects. Regulation of HIV transcription and mechanisims of latency. viral – host interactions. Use of lentiviruses for targeting specific cells for gene therpy application. - PowerPoint PPT PresentationTRANSCRIPT
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i. Regulation of HIV transcription and mechanisims of latency.
ii. viral – host interactions.iii. Use of lentiviruses for targeting specific cells for gene
therpy application.
• Dan Levy - Role of SETD6 in modulating HIV latency.
• Alon Freidman – Targeting of lentiviruses to specific cells.
Lost in transcription – mechanisms that drive HIV latency
Ongoing Projects
Ongoing Collaborations
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The Problem - latency is a block for HIV eradication
Latency - a reversibly low-productive state of infection, where infected cells retain the capacity to fully re-emerge and produce de-novo viral particles
New HIV infections
AIDS- related deaths
HAART
Pe
ople
Total: 34.2 million
HIV infected
Pe
ople
Latent HIV reservoirs that
are refractory to therapy
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What are the molecular mechanisms that regulate HIV latency?
Ways to reactivate latent HIV and eliminate viral reservoirs with
HAART?
Regulation of HIV transcriptional activation
Role of Positive transcription elongation b -PTEFb
HYPOTHESIS
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NF-ATTAFs…
Active State
HIV Provirus
gag
poltatrev
env nefvif
vpuvpr
5’LTR
Latent StateCondensed chromatin
HDACs
YY1/LSFCBF-1AP4
NF-AT
TAFs…
CpG islands
metH3K27
me3
SWI/SNFremodeling
HIV provirusCCR5/CXCR4 CD4
met met
P-TEFbHATs
HKMT/
SUV39H1
G9a
NF-B
Ac3’LTR Ac
Ac
met
nuc1
Ac
PRC1/2Remodeling
EZH2
NF-B
A
B
H3K9me2
Latency corresponds with transcription activation and chromatin state
Open chromatin
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HIV Tat - a master switch of viral transcription
CDK9
Cyclin T1
LTRRNA Polymerase II
PPP
P
P-TEFbHIV Tat
TAR
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RNAPII
TAR
Cdk9
P
PP
YSPTSPS
PCT
D
NELF
A-D
DSIF/
spt5P
ETATA
Sp1NFB
Tat
CycT1
AFF4
ELL2
ENL/
AF9
P
PAc
P
Cdk9CycT1
AAc
HIV LTR
SECIII
P
RelA/
p50
SEC
PAFc
AFF4
ELL2
Cdk9CycT
1 ENL/AF9
RNAPIImed
iato r
AP
II I
AFF4
ELL2
ENL/AF9
SEC
P
NF-BYEATS
motif
Cdk9
CycT1
Brd4
AAc
Tat independent (basal) Tat dependent
PID
TARP
P
TAR LTR
Recruitment modes of P-TEFb to the viral promoter
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•PKC activators (Bryostatin, Prostratin) •HDAC inhibitors ( SAHA)
•Bromodomain and extra-terminal (BET) bromodomain inhibitors (JQ1, I-BET)
•Hypertrophic or stress signals (UV), TCR ligation (IL-2/CD3 Ab)
•HIV infection
TatBrd4
MePCE LARP7
CycT1
Cdk9HEXIM1
HEXIM1
5’
7SKsnRNA
P PT270
S278
Ub
CycT1
Cdk9
Active state - free active P-TEFb
Resting stat - inactive P-TEFb
P T186
Cdk9
CycT1
P P
Ac
K380;386;390;404
P13K/Akt
3’
P-TEFb equilibrium in cells modulates HIV latency
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What are the molecular mechanisms that regulate HIV latency?
Ways to reactivate latent HIV and eliminate viral
reservoirs? Role of P-TEFb in establishment of HIV latency
Mechanisms that promote viralgene activation
identification of host factors that modulate HIV latency
Regulation of Transcriptional activation
1
2
3
Role of chromatin modulation (collaboration of D.Levy)
Screen for small molecules that can reactivate latent HIV
Modes of recruitment of P-TEFb to the viral promoter.
4