Regulation of HIV transcription and mechanisims of latency. viral – host interactions.
I.Regulation of HIV transcription and mechanisims of latency. ii.viral – host interactions....
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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 going Collaborations
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Transcript of I.Regulation of HIV transcription and mechanisims of latency. ii.viral – host interactions....
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
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
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
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
HIV Tat - a master switch of viral transcription
CDK9
Cyclin T1
LTRRNA Polymerase II
PPP
P
P-TEFbHIV Tat
TAR
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
•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
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.
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