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Updated: Aug 20, 2026
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity
Clodagh C O'Shea1, Leisa Johnson, Bridget Bagus
1UCSF Comprehensive Cancer Center, San Francisco, CA 94115, USA. coshea@cc.ucsf.edu
Abstract:
ONYX-015 is an adenovirus that lacks the E1B-55K gene product for p53 degradation. Thus, ONYX-015 was conceived as an oncolytic virus that would selectively replicate in p53-defective tumor cells. Here we show that loss of E1B-55K leads to the induction, but not the activation, of p53 in ONYX-015-infected primary cells. We use a novel adenovirus mutant, ONYX-053, to demonstrate that loss of E1B-55K-mediated late viral RNA export, rather than p53 degradation, restricts ONYX-015 replication in primary cells. In contrast, we show that tumor cells that support ONYX-015 replication provide the RNA export function of E1B-55K. These data reveal that tumor cells have altered mechanisms for RNA export and resolve the controversial role of p53 in governing ONYX-015 oncolytic selectivity.
Insights
ONYX-015, an oncolytic virus, selectively targets tumor cells by exploiting their defective RNA export mechanisms, not p53 degradation. This research clarifies the virus
Area of Science:
- Oncolytic virotherapy
- Molecular virology
- Cancer biology
Background:
- ONYX-015 is an adenovirus engineered to selectively replicate in tumor cells lacking functional p53.
- The precise mechanism governing its tumor selectivity has been debated, with roles attributed to p53 degradation and viral replication.
Purpose of the Study:
- To elucidate the role of the E1B-55K gene product in ONYX-015 replication and tumor selectivity.
- To investigate whether p53 degradation or other viral functions restrict ONYX-015 replication in primary cells.
Main Methods:
- Utilized a novel adenovirus mutant, ONYX-053, lacking the E1B-55K gene.
- Compared ONYX-015 and ONYX-053 replication in primary cells and tumor cells.
- Assessed p53 induction and activation in infected cells.
- Examined viral RNA export efficiency.
Main Results:
- Loss of E1B-55K in ONYX-015 leads to p53 induction but not activation in primary cells.
- The E1B-55K-mediated late viral RNA export function, not p53 degradation, restricts ONYX-015 replication in primary cells.
- Tumor cells supporting ONYX-015 replication possess functional E1B-55K RNA export mechanisms.
Conclusions:
- Tumor cells exhibit altered RNA export mechanisms that are exploited by ONYX-015.
- The E1B-55K protein's role in facilitating viral RNA export is critical for ONYX-015 replication in tumor cells.
- This study resolves the controversy surrounding p53's role in ONYX-015 oncolytic selectivity, highlighting RNA export as the key factor.
