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Review
. 2015 Nov 6;7(11):5767-79.
doi: 10.3390/v7112905.

Oncolytic Replication of E1b-Deleted Adenoviruses

Pei-Hsin Cheng  1 , Stephen L Wechman  2 , Kelly M McMasters  3   4 , Heshan Sam Zhou  5   6   7
Affiliations
Review

Oncolytic Replication of E1b-Deleted Adenoviruses

Pei-Hsin Cheng et al. Viruses. .

Abstract

Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viralmRNAexport, and cell cycle disruption.

Keywords: E1B; adenovirus; cancer selectivity; cell cycle; cyclin E; virotherapy.

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Figures

Figure 1
Figure 1
Depiction of the human Ad5 left end with various deletions in E1 genes. All the nucleotide coordinates refer to Ad5 (Genbank Accession No M73260). The wild-type Ad5 with the E1a and E1b genes and their endogenous promoters is shown at the top. The left inverted terminal repeat (ITR), packaging signal (Ψ), the E1a and E1b promoters (E1a-P and E1b-P), and the open reading frames are indicated. E1B19K and E1B55K have a small overlap. The solid lines represent Ad regions in these viruses, and the dashed lines represent the deleted regions. The restriction enzyme and the cleaving sites used to delete the E1 region are shown. Ad dl1520 carries native E1A promoter (E1A-P) to drive E1A expression and an 827-bp deletion with a point mutation to generate a premature stop codon in the E1B55K coding region.
Figure 2
Figure 2
Cyclin E upregulation in cancer cells supports oncolytic replication of E1b55K-deleted Ads. (A) In normal cells, Ad E1B55K functions to enhance cyclin E expression for virus replication. E1B55K may target cellular factors which, in turn, activate the cyclin E promoter for induction of the gene expression. Without E1B55K-induced cyclin E expression, replication of E1b55K-deleted Ads is repressed in normal cells; (B) In cancer cells, the cellular factors may already be activated or there are E1B55K-like factors to relax cyclin E regulation. Thus, E1B55K protein is not required to induce cyclin E expression in cancer cells. Cyclin E induced by Ad infection binds to and activates CDK2, which subsequently phosphorylates the transcriptional repressor retinoblastoma protein (pRb), leading to regulative expression of multiple genes (including the feedback upregulation of cyclin E) to provide a suitable cellular environment for oncolytic replication.
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