Abstract
Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I–III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.
Highlights
The survival of every organism requires the inheritance of genetic information during reproduction and the ability to adapt to more efficient replication in a changing environment
Virus recognition by the antiviral protein kinase R (PKR) and ribonuclease L (RNAse L) proteins contribute to translational inhibition observed in most strains of Mammalian orthoreovirus (MRV), but at least one additional stress kinase is necessary for the formation of stress granules (SGs) [68,73]
These findings suggest that an intact and activated integrated stress response (ISR), including the downstream effects of P-eIF2α, activating transcription factor 4 (ATF4), and PKR-like endoplasmic reticulum kinase (PERK) benefits MRV replication
Summary
The survival of every organism requires the inheritance of genetic information during reproduction and the ability to adapt to more efficient replication in a changing environment. Since viruses are obligate intracellular parasites, this results in dynamic interactions between viruses and their hosts Both are subject to the law of natural selection, pitting viruses and their hosts against one another as viruses evolve to better infect and replicate within a host that evolves to more efficiently inhibit viral disease. MRV is generally considered a clinically benign virus and has been used as a model for the investigation of the structure, function, and host interactions of members of the Reoviridae family of viruses for many years. While MRV was originally thought to primarily kill tumor cells through direct lysis, further investigation in vitro, in preclinical, and in clinical trials has shown that MRV infection of tumor cells elicits an antitumor immune response that is thought to play a major role in the cancer-killing ability of the virus [12,13]. Paclitaxel: [23] Paclitaxel: [23] Pemetrexed: [25] Docetaxel: [26] Paclitaxel: [23] Paclitaxel: [23] Paclitaxel: [23]
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