Abstract
The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrated the preferential replication of reovirus in transformed cell lines but not in normal cells. Later investigations have revealed the involvement of activated Ras signaling pathways (both upstream and downstream) and key steps of the reovirus infectious cycle in promoting preferential replication in cancer cells with reovirus-induced cancer cell death occurring through necrotic, apoptotic, and autophagic pathways. There is increasing evidence that reovirus-induced antitumor immunity involving both innate and adaptive responses also contributes to therapeutic efficacy though this discussion is beyond the scope of this article. Here, we review our current understanding of the mechanism of oncolysis contributing to the broad anticancer activity of reovirus. Further understanding of reovirus oncolysis is critical in enhancing the clinical development and efficacy of reovirus.
Highlights
REOVIRUS STRUCTURE Reovirus is a member of the Reoviridae family of viruses whose name was coined in 1959 and derived from the fact that it is commonly isolated from the respiratory and enteric tract without an association with clinical symptoms, or an orphan virus, infection can be associated with mild respiratory and enteric symptoms in humans [1,2,3,4,5]
These studies highlight two important points regarding reovirus oncolysis: [1] prior studies implicate the Ras/RalGEF/p38 pathway in the promotion of reovirus oncolysis independent of Raf and Jun NH2-terminal protein kinase (JNK) signaling, MEK/extracellular signal regulated kinases (ERKs), and JNK appear to have roles in reovirus infectivity and reovirus-induced apoptosis, and [2] further understanding of the reovirus infectious cycle has demonstrated that Ras-transformation affects multiple steps of the cycle, in addition to viral translation, such as viral uncoating or disassembly, generation of viral progeny with enhanced infectivity, release of progeny through enhanced apoptosis, and viral spread in subsequent rounds of infection (Figure 2) [31, 33, 38,39,40,41,42]
Reovirus is a double-stranded RNA (dsRNA) virus whose mechanism of oncolysis remains unclear though activated Ras signaling, involving upstream and downstream mediators, appears important to permissiveness to reovirus replication
Summary
REOVIRUS STRUCTURE Reovirus is a member of the Reoviridae family of viruses whose name was coined in 1959 and derived from the fact that it is commonly isolated from the respiratory and enteric tract without an association with clinical symptoms, or an orphan virus, infection can be associated with mild respiratory and enteric symptoms in humans [1,2,3,4,5]. The virus is transported to early and late endosomes where it undergoes proteolytic disassembly and degradation of the outer shell proteins sigma 3 (σ3) and mu 1 (μ1), in particular, by cysteine cathepsin proteases resulting in the formation of infectious subvirion particles (ISVPs) and in the release of transcriptionally active viral core particles, mediated by cleavage fragments of viral capsid proteins, into the cytoplasm [16,17,18,19,20]. Activated RNA-dependent RNA polymerase begins primary transcription within the core particles resulting in the release of primary transcripts that, along with protein products of early translation, form complexes or inclusions where further transcription and translation occur which, in turn, lead to viral replication and assembly, host cell death, and progeny release [1, 2, 4,5,6,7]. The events following virus internalization, endocytic processing, and viral core release remain poorly understood (Figure 1)
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