“A new family of compounds that reactivate
latent HIV in central memory T cells”
Vicente Planelles
University of Utah
Viral reactivation
Stimulus
Cellular activation
Proliferation
Cytokine secretion
Chemical Screen Using Tcm
Chemical Screen Using Tcm
GFP
DHIV construct
LTR
gag
rev
vif
LTR
tat
pol
vpr
nef
env
vpu
pLET-LAI (HIV-1 env expression construct)
LTR
tat/rev
HIV-1 env
HBV p(A)
Chemical Screen Using Tcm
Chemical Screen Using Tcm
Pos. controls
Neg. controls
Initial Characterization of Hydroxybenzotriazole
Benzotriazole
Derivatives
Potentiate
gc-Cytokine Signalig
Initial
Characterization
of
Hydroxybenzotriazole
Benzotriazole
Analogues
Benzotriazole Derivatives Do Not Induce
Benzotriazole
Derivativesof
Potentiate
gc-Cytokine Signalig
Initial Characterization
Hydroxybenzotriazole
Cell Activation or Proliferation
IL-2 + HOAt
IL-2 + HOAt
IL-2 + HOAt
Benzotriazole
Derivatives
Potentiate
gc-Cytokine
Signalig
Benzotriazole
as a Scaffold
for Chemical
Synthesis
Initial
Characterization
of
Hydroxybenzotriazole
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-1YL) - acetohydrazide derivatives as antimicrobial agents. Int. J.
Drug Dev. & Res. 4:322 (2012).
(Anti-microbial)
Benzotriazole Derivatives Potentiate gc-Cytokine Signaling
HOAt 100 mM
Benzotriazole Derivatives Potentiate gc-Cytokine Signaling
HOAt 100 mM
The JAK1,3 / STAT5 Pathway
Persistent STAT5 Phosphorylation
HOAt
IL-2
IL-2 + HOAt
Cytokine Secretion
G-CSF
GM-CSF
IL - 4
IL - 6
IL - 8
IL - 10
IL - 15
IL - 17A
MCP - 1
MIP - 1a
TNF - a
HOAt Reactivates Virus in Aviremic Patient Cells
N. Archin and D. Margolis
Novel
Novel pathways
do pathways
exist that do
canexist
separate viral from
that can separate
viral activation
from cellular activation
cellular
We just
to keep
an open
mind…
Weneed
just need
an open
mind
and then…
… wonderful, unexpected things can happen
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