Abstract:
:Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.
journal_name
PLoS Pathogjournal_title
PLoS pathogensauthors
Zakaria C,Sean P,Hoang HD,Leroux LP,Watson M,Workenhe ST,Hearnden J,Pearl D,Truong VT,Robichaud N,Yanagiya A,Tahmasebi S,Jafarnejad SM,Jia JJ,Pelin A,Diallo JS,Le Boeuf F,Bell JC,Mossman KL,Graber TE,Jaramillo M,doi
10.1371/journal.ppat.1007264subject
Has Abstractpub_date
2018-08-23 00:00:00pages
e1007264issue
8eissn
1553-7366issn
1553-7374pii
PPATHOGENS-D-17-02275journal_volume
14pub_type
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