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Viral reactivation

“A new family of compounds that reactivate latent HIV in central memory T cells” Vicente Planelles University of Utah. Viral reactivation. Cellular activation Proliferation Cytokine secretion. Stimulus. Chemical Screen Using Tcm. GFP. rev. gag. vif. LTR. LTR. tat. pol. nef.

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Viral reactivation

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

  2. Viral reactivation Cellular activation Proliferation Cytokine secretion • Stimulus

  3. Chemical Screen Using Tcm • GFP • rev • gag • vif • LTR • LTR • tat • pol • nef Chemical Screen Using Tcm • vpr • env • vpu • DHIV construct • pLET-LAI (HIV-1 env expression construct) HIV-1 env • HBV p(A) • tat/rev • LTR

  4. Chemical Screen Using Tcm Chemical Screen Using Tcm • Pos. controls • Neg. controls

  5. Initial Characterization of Hydroxybenzotriazole

  6. Initial Characterization of Hydroxybenzotriazole Benzotriazole Analogues Benzotriazole Derivatives Potentiate gc-Cytokine Signalig

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

  8. Initial Characterization of Hydroxybenzotriazole Benzotriazole Derivatives Potentiate gc-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 gc-Cytokine Signaling HOAt 100 mM

  10. Benzotriazole Derivatives Potentiate gc-Cytokine Signaling HOAt 100 mM

  11. The JAK1,3 / STAT5 Pathway

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

  13. Cytokine Secretion Bryostatin aCD3/aCD28 HOAt G-CSF GM-CSF IL - 4 IL - 6 IL - 8 IL - 10 IL - 15 IL - 17A MCP - 1 MIP - 1a TNF - a

  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 • Novel pathways do exist that can separate viral from cellular activation • We just need to keep an open mind… 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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