HOST FACTORS CONTROLLING VIRUS INFECTION: IMPLICATIONS FOR ANTIVIRALS AND VIROTHERAPY

Viruses are obligate intracellular parasites rely heavily on host components and pathways for their replication. Studying different cellular factors affecting viral infection can enable us to identify novel drug targets, improve current antiviral treatments and improve efficacy of virus based therapies. This dissertation examines two prototypic members of an order Mononegavirales, vesicular stomatitis virus (VSV) and Sendai virus (SeV) and is focused on: 1) resistance of some hosts to a broad spectrum antiviral drug ribavirin and 2) resistance of some pancreatic cancers to oncolytic virotherapy. Here, for the first time we examined whether certain cell types are naturally resistant to ribavirin even without prior drug exposure. Our results show striking differences between cell types in their response to ribavirin. Our data also suggest that this resistance was due to cellular factors rather than viral determinants and ribavirin may inhibit the same virus via different mechanisms in different cells depending on the ribavirin metabolism. Additionally, resistance of oncolytic VSV therapy in specific human pancreatic ductal adenocarcinoma (PDA) cells was investigated and this resistance was attributed to constitutive expression of the IFN-stimulated antiviral genes MxA and OAS. Decreasing the levels of MxA and OAS by inhibition of JAK/STAT signaling, improved VSV infection and oncolysis. Overall, our study demonstrated heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other oncolytic viruses (OVs) sensitive to type I IFN responses