Vicente Planelles University of Utah Viral reactivation Stimulus Cellular activation Proliferation Cytokine secretion LTR LTR gag pol vif vpr env vpu nef rev tat DHIV construct pLETLAI HIV1 env expression construct ID: 380515
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Slide1
“A new family of compounds that reactivate latent HIV in central memory T cells”Vicente PlanellesUniversity of UtahSlide2
Viral reactivation
Stimulus
Cellular activation
Proliferation
Cytokine
secretionSlide3
LTR
LTR
gag
pol
vif
vpr
env
vpu
nef
rev
tat
DHIV construct
pLET-LAI (HIV-1 env expression construct)
LTR
tat/rev
HIV-1
env
HBV p(A)
GFP
Chemical Screen Using Tcm
Chemical Screen Using TcmSlide4
Neg. controls
Pos. controls
Chemical Screen Using Tcm
Chemical Screen Using TcmSlide5
Initial Characterization of HydroxybenzotriazoleSlide6
Initial Characterization of Hydroxybenzotriazole
Benzotriazole Derivatives Potentiate
g
c-Cytokine Signalig
Benzotriazole AnaloguesSlide7
IL-2 + HOAt
IL-2 + HOAt
IL-2 + HOAt
Initial Characterization of Hydroxybenzotriazole
Benzotriazole Derivatives Potentiate
g
c-Cytokine Signalig
Benzotriazole Derivatives Do Not Induce
Cell Activation or ProliferationSlide8
Initial Characterization of HydroxybenzotriazoleBenzotriazole Derivatives Potentiate
g
c-Cytokine Signalig
Benzotriazole as a Scaffold for Chemical Synthesis
Carta et al.
Synthesis and antiproliferative activity of 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles variously substituted. Farmaco
59:
637 (2004).
(Anti-proliferative
)
Patel et al.
Synthesis of novel
N-substituted 2-(1H-benzotriazol-1-YL) - acetohydrazide derivatives as antimicrobial agents. Int. J. Drug Dev. & Res. 4:322 (2012).(Anti-microbial)Slide9
Benzotriazole Derivatives Potentiate
g
c-Cytokine Signaling
HOAt 100
m
M Slide10
HOAt 100 m
M
Benzotriazole Derivatives Potentiate
g
c-Cytokine SignalingSlide11
The JAK1,3 / STAT5 PathwaySlide12
Persistent STAT5 Phosphorylation
IL-2 + HOAt
IL-2
HOAt Slide13
Cytokine Secretion
G-CSF
GM-CSF
IL - 4
IL - 6
IL - 8
IL - 10
IL - 15
IL - 17A
MCP - 1
MIP - 1
a
TNF -
a
a
CD3/
a
CD28
Bryostatin
HOAtSlide14
HOAt Reactivates Virus in Aviremic Patient Cells
N. Archin and D. MargolisSlide15
Novel pathways do exist that can separate viral from cellular activationWe just need to keep an open mind…
Novel pathways do exist
that can separate viral from cellular activation
We just need an open mind and then
…
… wonderful, unexpected things can happenSlide16
Acknowledgments
Peter Ramirez
Laura Martins
Patrick
Cassiday
Adam Spivak
Bia
Silva
Matt Szaniawski
Ani
Schjelderup
Bosque Lab (UU)
Camille Novis
UNC
David Margolis
Nancie
Archin
UC Davis
Paul
Luciw
NIAID