Genetically engineered HSV in the treatment of glioma: a review

Herpes simplex virus (HSV)2 entry into the cell occurs by fusion, and requires a multipartite apparatus made of a glycoprotein quartet: gD, gB, and the heterodimer gH/gL; for reviews, see Refs. 1-3). When ectopically expressed, the four glycoproteins mediate cell-cell fusion (4). gD serves as the receptor-binding glycoprotein and interacts with three alternative receptors, nectin1, herpesvirus entry mediator (HVEM) and modified heparan sulfate (5-8). It also represents the key player in the triggering of fusion, i.e. in inducing fusion execution by gB and gH/gL (9 -12). These are among the most highly conserved proteins across the Herpesviridae family and constitute the fusion core apparatus. Their respective roles in fusion execution are unclear at present. Thus, gH carries elements typical of fusion glycoproteins, i.e. hydrophobic regions able to interact with target cells or artificial membranes and two heptad repeats potentially able to form a coiled coil (13-18). Peptides mimicking the hydrophobic regions of gH promote fusion of artificial membranes (19,20). With respect to gB, the crystal structure shows a trimer with a central coiled-coil and an overall structure similar to that of the fusion glycoprotein G of vesicular stomatitis virus in its postfusion conformation (21,22). Recently, a receptor for gB was described (23). Of note, although for virus-to-cell entry and for cell-cell fusion, fusion requires the simultaneous presence of gB and gH/gL, fusion of perinuclear virions with the outer nuclear membranes appears to necessitate either gH/gL or gB (24). Furthermore, it has been reported that HSV fusion may be preceded by a hemifusion intermediate mediated by gD and gH/gL (25).A major focus of current research is definition of proteinprotein interactions. With respect to HSV entry/fusion, to understand how the four glycoproteins cross-talk to each other, it is pivotal to detect which complexes are formed by the glycoproteins in their prefusion and fusion-active conformations, and, ultimately, the chain of interactions that signal the gD encounter with its cellular receptor and culminate in activation of gB and gH/gL. The proposed model of gD-activated entry/ fusion (2, 9 -12, 26, 27) envisions that (i) gD ectodomain is organized in two functionally and topologically distinct regions, the N-terminal one, spanning amino acids (aa) 1 to ϳ240/260, carrying the receptor binding sites, and the C-terminal one (aa 240/260 -310), carrying the profusion domain required for fusion but not for receptor binding; (ii) the unliganded gD adopts an auto-inhibited conformation, whereby the C-terminal domain folds around the N-terminal one and occupies or hinders the receptor-binding sites; (iii) gD undergoes a closed-to-open switch in conformation, whereby the C-terminal domain is dislodged from its binding site and

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“…We analyzed neural glioblastoma U251 cells and human fibroblasts. Glioblastoma is the target of HSV oncolytic virotherapy (52). Fig.…”

Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus gD Forms Distinct Complexes with Fusion Executors gB and gH/gL in Part through the C-terminal Profusion Domain

Gianni

Amasio

Campadelli-Fiume

2009

Journal of Biological Chemistry

100

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“…In phase I clinical trials, ␥ 1 34.5-deleted HSV was administered i.t. in various tumors, and stereotactically in gliomas; a therapeutic effect was noticed irrespective of the serostatus or seroconversion of patients (2,3).…”

Section: Discussionmentioning

confidence: 99%

“…S ince the pioneering observation that a genetically modified herpes simplex virus (HSV) exerts a therapeutic effect against glioblastoma (1), oncolytic virotherapy has entered clinical experimentation (2)(3)(4)(5)(6)(7). Ideally, the oncolytic virus is genetically reprogrammed to target tumor cells and spare normal cells (4,8,9).…”

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confidence: 99%

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Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Menotti

Nicoletti

Gatta

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

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Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumorspecific by deletion of selected genes or retargeting to tumorspecific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD 50 >5 ؋ 10 8 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD 50 Ϸ 5 ؋ 10 4 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies. mammary carcinoma ͉ ovary carcinoma ͉ retarget ͉ tropism

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“…Thus, HSV is a promising virus for use as an oncolytic agent in the therapy of glioblastoma and as a lytic agent in the therapy of restenosis (18,29). Some applications are under phase I clinical experimentation.…”

Section: Discussionmentioning

confidence: 99%

Entry of Herpes Simplex Virus Mediated by Chimeric Forms of Nectin1 Retargeted to Endosomes or to Lipid Rafts Occurs through Acidic Endosomes

Gianni

Campadelli-Fiume

Menotti

2004

J Virol

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Herpes simplex virus (HSV) enters cells by fusion with target membranes, commonly the plasma membrane.In some cells, including CHO cells expressing the nectin1 or herpesvirus entry mediator receptors, entry occurs through an endocytic route. We report the following results. (i) When expressed in J cells, nectin1 and HVEM mediated a pathway of entry insensitive to endosome acidification inhibitors. (ii) A chimeric nectin1 receptor competent for endosomal uptake by fusion of the nectin1 ectodomain with the transmembrane sequence and cytoplasmic tail of the epidermal growth factor receptor (EGFR1) (nectin1-EGFR1) and chimeric nectin1 sorted to lipid rafts by a glycosylphosphatidylinositol anchor mediated endocytic entry blocked by the early endosome inhibitor wortmannin and by the endosome acidification inhibitors bafilomycin and NH 4 Cl. (iii) Entry mediated by nectin1-EGFR1 was selectively inhibited by AG1478, a tyrosine phosphorylation inhibitor that targets the EGFR1 cytoplasmic tail and blocks the signaling pathway that culminates in clathrindependent uptake of the receptor into endosomes. We draw the following conclusions. (i) The same receptor may initiate different routes of infection, depending on the cell in which it is expressed. Hence, the cell is a determinant that controls whether a given receptor initiates a plasma membrane or an endocytic route of entry.(ii) Receptors whose physiology involves uptake into endosomes or sorting to lipid rafts are suitable to serve as HSV receptors. (iii) Structural features of the receptors are additional determinants that control whether HSV entry occurs at the plasma membrane or at endosomes. These findings are relevant to studies of HSV retargeting to specific receptors.Herpes simplex virus (HSV) enters cells by fusion of the envelope with target membranes. This event follows virus attachment mediated by the binding of glycoprotein C (gC) to the glycosaminoglycan moieties of heparan sulfate proteoglycan and requires virion envelope gD as the receptor-binding glycoprotein (3,31). gD interacts with two alternative protein receptors, nectin1, an intercellular adhesion molecule belonging to the immunoglobulin (Ig) superfamily, and herpesvirus entry mediator (HVEM), a member of the tumor necrosis factor receptor family (7,11,16,25). The crystal structure of the gD ectodomain showed that it is made of an Ig-folded core with N-and C-terminal extensions (4). The N terminus is disordered in the crystal of gD alone and forms a hairpin when gD is bound to HVEM, testifying to a conformational modification in gD following receptor binding (4). The interaction of gD with its receptor triggers fusion. According to a current model, the triggering event is a conformational modification that ensues in gD after receptor binding, such that the profusion domain of gD, which is proline rich and located membrane proximally in the ectodomain, can recruit or activate three additional fusion glycoproteins, gH, gL, and gB (5). These glycoproteins are conserved throughout the family Herpesvir...

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Genetically engineered HSV in the treatment of glioma: a review

Cited by 80 publications

References 49 publications

Herpes Simplex Virus gD Forms Distinct Complexes with Fusion Executors gB and gH/gL in Part through the C-terminal Profusion Domain

Herpes Simplex Virus gD Forms Distinct Complexes with Fusion Executors gB and gH/gL in Part through the C-terminal Profusion Domain

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Entry of Herpes Simplex Virus Mediated by Chimeric Forms of Nectin1 Retargeted to Endosomes or to Lipid Rafts Occurs through Acidic Endosomes

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