*3.4. The Autophagic Response to Viral Infections*

There is growing evidence that the role of autophagy in the infectious cycle of many viruses is critical. Autophagy is an evolutionary conserved adaptive process in which the cells attempt to maintain their homeostasis [79,80]. It can be triggered by different types of stress, such as hypoxia, nutrient deprivation and infection [81]. The role of autophagy is to remove detrimental cytosolic material such as protein aggregates and damaged organelles. During this process, a phagophore engulfs cytosolic material to form an autophagosome, which subsequently fuses with a lysosome to degrade its cytoplasmic content [81].

Autophagy is activated by the infected cell to degrade and remove the virions from the cell, a process called xenophagy [82]. TLRs, RLRs and cGAS signaling pathways, among others, lead to autophagy activation to enhance the interferon production and create an anti-viral milieu [83]. Notably, plasmacytoid dendritic cells (pDCs) which lack the autophagy protein 5 (Atg5) showed decreased TLR7-dependent IFNα and IL-12 production after VSV and Sendai virus infection, indicating the importance of autophagy for mounting an anti-viral response [84]. Additionally, autophagy was shown to have anti-viral effects against Sindbis virus and Rift Valley Fever Virus infection [85,86]. On the other hand, many viruses have developed mechanisms to exploit autophagy in favor of their viral replication. For example, herpesvirus and dengue virus were shown to enhance autophagy to promote cell survival in order to establish a successful infection and enhanced viral replication [87,88]. Moreover, rapamycin, an autophagy inducer, was shown to increase the viral replication of various oncolytic viruses in tumor cells, including adenovirus, reovirus, poliovirus, herpes virus, NDV and myxoma virus [89–94]. In line with these findings, it was shown that knocking out two key autophagy genes (ATG5 or ATG10) impaired virus-induced lysis of cancer cells by a modified oncolytic adenovirus (delta24-RGD) [95]. Furthermore, co-treatment with Everolimus, a rapamycin derivative, and delta24-RGD enhanced autophagic dependent cell death in an in vivo glioma model [96].

The double-sided role of autophagy in oncolytic virus efficacy has captured the attention of the research community and it has been extensively reviewed [97,98]. The results thus far suggest that, for certain OVs, the tumor cells' ability to activate autophagy can contribute to the degree of viral replication, and ultimately the therapeutic efficacy of the viral treatment.
