Regulation of HIV transcription and mechanisims of latency.

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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.
• Dan Levy - Role of SETD6 in modulating HIV
  latency.
• Alon Freidman Targeting of lentiviruses to
  specific cells.

Ongoing Collaborations
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The Problem - latency is a block for HIV
eradication
Latent HIV reservoirs that are refractory to
therapy
Latency - a reversibly low-productive state of
infection, where infected cells retain the
capacity to fully re-emerge and produce de-novo
viral particles
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What are the molecular mechanisms that regulate
HIV latency ?
Regulation of HIV transcriptional activation
HYPOTHESIS
Role of Positive transcription elongation b -PTEFb
Ways to reactivate latent HIV and eliminate viral
reservoirs with HAART ?
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Latency corresponds with transcription activation
and chromatin state
A
Active State
NF-kB
Open chromatin
SWI/SNF remodeling
HIV Provirus
rev
5LTR
3LTR
vif
tat
env
pol
nef
vpr
vpu
B
Latent State
Condensed chromatin
NF-kB
PRC1/2 Remodeling EZH2
YY1/LSF CBF-1 AP4
met
H3K9 me2
CpG islands
nuc1
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TAR
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Recruitment modes of P-TEFb to the viral promoter
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P-TEFb equilibrium in cells modulates HIV latency

• 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

T270 S278
Ub
T186
3
K380386390404
Resting stat - inactive P-TEFb
Active state - free active P-TEFb
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What are the molecular mechanisms that regulate
HIV latency ?
Regulation of Transcriptional activation
Ways to reactivate latent HIV and eliminate viral
reservoirs ?
Role of P-TEFb in establishment of HIV latency
1
Mechanisms that promote viral gene activation
2
Role of chromatin modulation (collaboration of
D.Levy)
3
Modes of recruitment of P-TEFb to the viral
promoter.
Screen for small molecules that can reactivate
latent HIV
identification of host factors that modulate HIV
latency
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