Basal ISG Expression Diminishes oHSV Productivity

Interferon-stimulated genes (ISG) encode diverse proteins that mediate intrinsic antiviral resistance in infected cells. Here it was hypothesized that malignant peripheral nerve sheath tumor (MPNST) cells resist the productive infection of oncolytic herpes simplex virus (oHSV) through activation of the JAK/STAT1 pathway and resultant upregulation of ISGs. Multiple human and mouse MPNST cells were used to explore the relationship between STAT1 activation and the productive infection of 134.5 oHSVs. STAT1 activation in response to oHSV infection was found to associate with diminished 134.5 oHSVs replication and spread. Multiday pretreatment, but not cotreatment, with a JAK inhibitor significantly improved viral titer and spread. ISG expression was found to be elevated prior to infection and downregulated when treated with the inhibitor, suggesting that the JAK/STAT1 pathway is active prior to infection. Conversely, upregulation of ISG expression in normally permissive cells significantly decreased oHSV productivity. Finally, a possible link between NF-B pathway activation and ISG expression was established through the expression of inhibitor of kB (IB) which decreased basal STAT1 transcription and ISG expression. These results demonstrate that basal ISG expression prior to infection contributes to the resistance of 134.5 oHSVs in MPNST cells. Implications: Although cancer-associated ISG expression has been previously reported to impart resistance to chemotherapy and radiotherap...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signal Transduction Source Type: research