Targeting JAK/STAT signaling antagonizes resistance to oncolytic reovirus therapy driven by prior infection with HTLV-1 in models of T-cell lymphoma

Shariful Islam, Claudia M. Espitia, Daniel O. Persky, Jennifer S. Carew, Steffan T. Nawrocki

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.

Original languageEnglish (US)
Article number1406
JournalViruses
Volume13
Issue number7
DOIs
StatePublished - Jul 2021

Keywords

  • HTLV-1
  • Oncolytic virus
  • Pelareorep
  • Reolysin
  • Reovirus
  • T-cell lymphoma

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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