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“A new family of compounds that reactivate latent HIV in central memory T cells” Vicente Planelles University of Utah.

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Presentation on theme: "“A new family of compounds that reactivate latent HIV in central memory T cells” Vicente Planelles University of Utah."— Presentation transcript:

1 “A new family of compounds that reactivate latent HIV in central memory T cells” Vicente Planelles University of Utah

2 Viral reactivation Stimulus Cellular activation Proliferation Cytokine secretion

3 LTR gag pol vif vprenv 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

4 Neg. controls Pos. controls Chemical Screen Using Tcm

5 Initial Characterization of Hydroxybenzotriazole

6 Benzotriazole Derivatives Potentiate  c-Cytokine Signalig Benzotriazole Analogues

7 IL-2 + HOAt Initial Characterization of Hydroxybenzotriazole Benzotriazole Derivatives Potentiate  c-Cytokine Signalig Benzotriazole Derivatives Do Not Induce Cell Activation or Proliferation

8 Initial Characterization of Hydroxybenzotriazole Benzotriazole Derivatives Potentiate  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)

9 Benzotriazole Derivatives Potentiate  c-Cytokine Signaling HOAt 100  M

10 Benzotriazole Derivatives Potentiate  c-Cytokine Signaling

11 The JAK1,3 / STAT5 Pathway

12 Persistent STAT5 Phosphorylation IL-2 + HOAt IL-2 HOAt

13 Cytokine Secretion G-CSF GM-CSF IL - 4 IL - 6 IL - 8 IL - 10 IL - 15 IL - 17A MCP - 1 MIP - 1  TNF -   CD3/  CD28 Bryostatin HOAt

14 HOAt Reactivates Virus in Aviremic Patient Cells N. Archin and D. Margolis

15 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

16 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


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