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Open Access Publications from the University of California

Cellular Signaling Analysis shows antiviral, ribavirin-mediated ribosomal signaling modulation.

  • Author(s): Ding, Xianting
  • Krutzik, Peter O
  • Ghaffari, Amir Ali
  • Zhaozhi, Yixiu
  • Miranda, Daniel
  • Cheng, Genhong
  • Ho, Chih-Ming
  • Nolan, Garry P
  • Sanchez, David Jesse
  • et al.

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As antiviral drug resistance develops and new viruses emerge there is a pressing need to develop strategies to rapidly develop antiviral therapeutics. Here we use phospho-specific flow cytometry to assess perturbations of many different cellular signaling pathways during treatment with drug combinations that are highly effective in blocking Herpes simplex virus type 1 (HSV-1) infection. We discovered two antiviral drug combinations act on distinct signaling pathways, either STAT1 or S6 phosphorylation, to block HSV-1 infection. We focused on upregulation of S6 phosphorylation by HSV-1 infection, and our subsequent finding that ribavirin antagonizes this upregulation of S6 phosphorylation. We go on to show that the S6 kinase inhibitor SL0101 blocks HSV-1 replication in vitro and in an in vivo animal model of HSV-1 infection. Overall, we have used an unbiased analysis of cellular signaling pathways during treatment by antiviral drug combinations to discover a novel antiviral drug target against HSV-1 infection. The outcomes of the approach we present highlight the importance of analyzing how antiviral drugs modulate cellular and pathogen-induced signaling as a method to discover new drug therapy targets.

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