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“A new family of compounds that reactivate latent HIV in central memory T cells”
Vicente PlanellesUniversity of Utah
Viral reactivation
StimulusCellular activationProliferationCytokine secretion
LTRLTRgag
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 Tcm
Neg. controls
Pos. controls
Chemical Screen Using Tcm Chemical Screen Using Tcm
Initial Characterization of Hydroxybenzotriazole
Initial Characterization of HydroxybenzotriazoleBenzotriazole Derivatives Potentiate gc-Cytokine SignaligBenzotriazole Analogues
IL-2 + HOAt
IL-2 + HOAt
IL-2 + HOAt
Initial Characterization of HydroxybenzotriazoleBenzotriazole Derivatives Potentiate gc-Cytokine SignaligBenzotriazole Derivatives Do Not Induce Cell Activation or Proliferation
Initial Characterization of HydroxybenzotriazoleBenzotriazole Derivatives Potentiate gc-Cytokine SignaligBenzotriazole 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)
Benzotriazole Derivatives Potentiate gc-Cytokine Signaling
HOAt 100 mM
HOAt 100 mM
Benzotriazole Derivatives Potentiate gc-Cytokine Signaling
The JAK1,3 / STAT5 Pathway
Persistent STAT5 Phosphorylation
IL-2 + HOAt
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
aCD3/aCD28
Bryostatin
HOAt
HOAt Reactivates Virus in Aviremic Patient Cells
N. Archin and D. Margolis
Novel pathways do exist that can separate viral from cellular activation
We 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 happen
Acknowledgments
Peter RamirezLaura Martins
Patrick CassidayAdam Spivak
Bia SilvaMatt SzaniawskiAni Schjelderup
Bosque Lab (UU)Camille Novis
UNCDavid MargolisNancie Archin
UC DavisPaul Luciw
NIAID