Expression of a fusogenic membrane glycoprotein by an oncolytic herpes simplex virus potentiates the viral antitumor effect

Abstract

Oncolytic viruses have shown considerable promise in the treatment of solid tumors, but their potency must be improved if their full clinical potential is to be realized. We inserted the gene encoding a truncated form of the gibbon ape leukemia virus envelope fusogenic membrane glycoprotein (GALV.fus) into an oncolytic herpes simplex virus, using an enforced ligation procedure. Subsequent in vitro and in vivo studies showed that expression of GALV.fus in the context of an oncolytic virus significantly enhances the antitumor effect of the virus. Furthermore, by controlling GALV.fus expression through a strict late viral promoter, whose activity depends on the initiation of viral DNA replication, we were able to express this glycoprotein in tumor cells but not in normal nondividing cells. It will be of interest to confirm whether functional expression of a strong fusogenic gene by an oncolytic herpes simplex virus enhances viral antitumor activity without increasing its toxicity.

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

“…[1][2][3][4][7][8][9][10][11][12][13][14][15] In this study, we demonstrate that HERV-W FMGs' cytotoxicity resulting from the formation of gigantic cells is sufficient to induce tumor regression, with a very strong bystander effect, after non-viral, intratumoral gene delivery as previously described for GALV.…”

“…[4][5][6][7] In addition to this syncytia-mediated toxicity, FMG has also been shown to enhance the antitumor therapeutic activity of replicating adenovirus, oncolytic HSV and vesicular stomatitis virus. [8][9][10][11][12] FMG-induced cytotoxicity is not immediate. Multinucleated syncytia develop within 24 h after transfection and gradually die in 5 days.…”

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

“…Studies exploring chemotherapy-oncolytic virus combinations or viruses encoding therapeutic transgenes have demonstrated that synergistic tumor killing can either be replication-dependent, with enhanced replication resulting in enhanced potency, [4][5][6]9 or replication-independent, with enhanced potency being caused by mechanisms other than enhanced viral replication. 7,8 We found that TSA had a suppressive effect on the growth of oral SCC cells at 0.3 mM, but its effect was insufficient at 0.1 mM.…”

“…Thus, recent studies have focused on the effect of combining oncolytic virotherapy with chemotherapy or construction of viruses encoding therapeutic transgenes. [4][5][6][7][8][9] The ubiquitous nuclear factor NF-kB is a critical regulator of the expression of numerous genes implicated in immune and inflammatory responses, cellular proliferation and differentiation and cell survival. 10,11 It is activated by a broad variety of stimuli, such as growth factors, cytokines, ionizing radiation, ultraviolet light, chemotherapeutic drugs and bacterial and viral infections.…”

Replication-competent herpes simplex vectors: design and applications

“…To this purpose, it has been recently demonstrated that incorporation of cell membrane fusion capability into an oncolytic HSV can significantly increase the antitumor potency of the virus. [57][58][59] These oncolytic HSVs were constructed by three different methods: (i) screening for the syncytial phenotype after random mutation of a well-established oncolytic HSV (to obtain Fu-10); (ii) insertion of the gene encoding the hyperfusogenic membrane glycoprotein of gibbon ape leukemia virus (GALV.fus) into the genome of an oncolytic HSV (to generate Synco-2); and (iii) incorporation of both of these membrane fusion mechanisms into a single oncolytic HSV (to generate Synco-2D).…”