“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