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A compendium of adenovirus genetic modifications for enhanced replication, oncolysis, and tumor immunosurveillance in cancer therapy

Author:
Stepanenko, Aleksei A., Chekhonin, Vladimir P.
Source:
Gene 2018 v.679 pp. 11-18
ISSN:
0378-1119
Subject:
Adenoviridae, RNA interference, T-lymphocytes, amino acids, death, endoplasmic reticulum, epitopes, gene overexpression, genetic engineering, major histocompatibility complex, mutation, natural killer cells, neoplasms, progeny, proteins, sumoylation, therapeutics, tomatoes, viruses
Abstract:
In this review, we specifically focus on genetic modifications of oncolytic adenovirus 5 (Ad5)-based vectors that enhance replication, oncolysis/spread, and virus-mediated tumor immunosurveillance. The finding of negative regulation of minor core protein V by SUMOylation led to the identification of amino acid residues, which when mutated increase adenovirus replication and progeny yield. Suppression of Dicer and/or RNAi pathway with shRNA or p19 tomato bushy stunt protein also results in significant enhancement of adenovirus replication and progeny yield. Truncation mutations in E3-19K or i-leader sequence or overexpression of adenovirus death protein (ADP) potently increase adenovirus progeny release and spread without affecting virus yield. Moreover, E3-19K protein, which was found to inhibit both major histocompatibility complex I (MHCI) and MHC-I chain-related A and B proteins (MICA/MICB) expression on the cell surface, protecting infected cells from T-lymphocyte and natural killer (NK) cell attack, may be tailored to selectively target only MHCI or MICA/MICB, or to lose the ability to downregulate both. At last, E3-19K protein may be exploited to deliver tumor-associated epitopes directly to the endoplasmic reticulum for loading MHCI in the transporter associated with antigen processing (TAP)-deregulated cells.
Agid:
6134479