*3.3. Innate Anti-Viral Responses*

Upon cell entry, antiviral host defenses may be activated that counteract a productive lytic cycle and progeny production. There is a plethora of innate sensors that could lead to clearance of the infected cell and halt the viral spreading, leading to resistance to OV therapy. As soon as the cell is infected, the viral pathogen-associated molecular patterns (PAMPs) are sensed by pattern recognition receptors (PRRs). These PRRs include Toll-like receptors (TLRs) [65], RIG-I-like receptors (retinoic acid-inducible gene-I-like receptors, RLRs) [66], Ctype lectin receptors (CLRs) [66], oligomerization domain containing receptors {(NOD-like receptors (NLRs)} [66], cyclic GMP-AMP synthase (cGAS) [67] and absent in melanoma 2 (AIM2)-like receptors (ALRs) [68]. The recognition of the viral PAMPs from the host PRRs results in interferon type I (IFNα, IFNβ, IFN-ε, IFN-κ, IFN-ω, IFN-δ, IFN-ζ and IFN-τ) and interferon type III (IFN-λ*ς*) production, as well as the expression of interferon stimulated genes (ISGs) and other proinflammatory cytokines and chemokines [69,70].

Although the aforementioned PRRs have been extensively studied, not many studies have attempted to correlate their overexpression in tumor cells with OV resistance; but rather with the aftermath of the recognition, the antiviral interferon pathways. However, a few studies have implicated the cytosolic DNA sensing pathway to oncolytic herpes virus-1 resistance (see below). The main sensor of dsDNA in the cytoplasm is the cGAS, which recognizes dsDNA viruses and reverse transcribing RNA viruses like HIV-1. As soon as cGAS is activated, it synthesizes cGAMP which activates the adaptor protein stimulator of interferon genes (STING) [71]. Stimulation of STING leads to the activation of IRF3 and NFκB [71]. Interferon gamma inducible protein 16 (IFI16) is another sensor of dsDNA that signals via STING to activate IRF3 and NFκB resulting in IFNβ production [72].

Ultimately, viral detection by the aforementioned sensors will lead to the activation of host defenses such as the production of type I and type III interferons. These have distinct receptors, however, both activate a signaling cascade via receptor-associated protein tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which activate the activator of transcription 1 (STAT1) and STAT2, which subsequently form a complex with the IFN regulatory factor 9 (IRF9), the ISGF3 complex [73]. This complex translocates to the nucleus, resulting in the expression of more than 300 ISGs and pro-inflammatory molecules and establishing an anti-viral state in the infected cell [74,75]. The cytokine and chemokine milieu produced by the infected cell also acts in a paracrine manner to induce an ISG-mediated anti-viral state in the (uninfected) adjacent cells. Some of these ISGs, such as GTPase myxovirus resistance 1 (MxA), ribonuclease L (RNaseL) and protein kinase R (PKR) have direct antiviral activity. For instance, MxA monomers reside in the cytoplasm and upon binding to viral components can degrade them [76]. PKR regulates a plethora of signaling pathways and its role in antiviral response and inhibition of host translation is considered crucial upon virus infection [76].

The anti-viral IFNs are major determinants of OV efficacy. Many OVs exploit the IFN pathway defects to successfully replicate in tumor cells. For instance, it has been shown that STING pathway is correlated with oncolytic herpes virus-1 resistance (see below). However, new evidence shows that this advantage in viral replication may not correlate with tumor eradication in vivo [77]. This may be explained by the inability of oncolytic viruses to induce immunogenic cell death in STING-deficient tumor cells, thus hampering the induction of innate and adaptive immunity [78]. Identifying specific defects in the IFN pathway that may 'assist' the viral replication without harming the induction of antitumor immunity, could lead to identification of predictive biomarkers for OV sensitivity.
