Intergeneric poliovirus recombinants for the treatment of malignant glioma

Abstract

Poliovirus neuropathogenicity depends on sequences within the 5 nontranslated region of the virus. Exchange of the poliovirus internal ribosomal entry site with its counterpart from human rhinovirus type 2 resulted in attenuation of neurovirulence in primates. Despite deficient virus propagation in cells of neuronal origin, nonpathogenic polio recombinants retain excellent growth characteristics in cell lines derived from glial neoplasms. Susceptibility of malignant glioma cells to poliovirus may be mediated by expression of a poliovirus receptor, CD155, in glial neoplasms. Intergeneric polio recombinants with heterologous internal ribosomal entry site elements unfolded strong oncolytic potential against experimentally induced gliomas in athymic mice. Our observations suggest that highly attenuated poliovirus recombinants may have applicability as biotherapeutic antineoplastic agents.M alignant gliomas are the most common primary tumors of the central nervous system (1). Available treatment is of limited utility for these tumors, and prognosis is therefore poor (1). The resistance of malignant gliomas to conventional therapies has inspired the search for novel strategies, and recently, these strategies have involved animal viruses, either as attenuated variants of pathogenic species with direct oncolytic properties (2, 3) or as delivery vehicles for foreign genetic material (4 -6).Poliovirus is a nonenveloped plus-stranded RNA virus belonging to Picornaviridae and is the causative agent of paralytic poliomyelitis. The vast majority of poliovirus infections remain asymptomatic, but 1-2% of cases result in neurologic complications (7). Restriction of poliovirus cell tropism to lower motor neurons resident within the spinal cord and brainstem gives rise to a highly characteristic clinical syndrome dominated by flaccid paralysis. Selective targeting of motor neurons by poliovirus is most likely determined by the distribution of its cellular receptor, the Ig superfamily molecule CD155. This assumption is supported by the observation that mice transgenic for CD155 develop a polio-like syndrome after poliovirus infection (8-10). In addition, cell-internal conditions favoring viral replication may contribute to poliovirus cell-type specificity.The neuropathogenicity of poliovirus depends on the celltype-specific function of its internal ribosomal entry site (IRES) element in cells of neuronal origin (10). The IRES is part of the 5Ј nontranslated region not only of picornaviruses (11) but also of hepatitis C virus (12, 13). IRES elements assure initiation of translation in a 5Ј end-independent, cap-independent manner (14-16). We have demonstrated that IRES elements encode strong cell-type-specific restrictions toward virus propagation.This restriction is illustrated by the highly attenuated phenotype of intergeneric recombinant polioviruses carrying IRES elements derived from human rhinovirus type 2 (10, 17). We have demonstrated that a prototype intergeneric poliovirus chimera [called PV1(RIPO)] is characterized by exce...

Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf–MEK–ERK–AP-1 pathway

“…Thus, the expression of the human and mouse Necl-5 genes may be differently regulated by different transcription factors. However, since human Necl-5 is upregulated in human colorectal carcinoma and malignant glioma (Gromeier et al, 2000;Masson et al, 2001), the expression of human Necl-5 may be similarly regulated by oncogenic Ras and the Raf-MEK-ERK-AP-1 pathway through a putative AP-1-binding site outside the core promoter. Alternatively, the expression of human Necl-5 may be regulated by oncogenic Ras through other transcription factors such as Ets and CREB or a pathway different from the Raf-MEK-ERK pathway.…”

“…Human PVR/ CD155 was originally identified as the human PVR (Mendelsohn et al, 1989;Koike et al, 1990), whereas Tage4 was originally identified as the product of a gene overexpressed in rat and mouse colon carcinoma (Chadeneau et al, 1994(Chadeneau et al, , 1996. PVR/CD155 has subsequently been shown to be overexpressed in human colorectal carcinoma and malignant glioma (Gromeier et al, 2000;Masson et al, 2001). This molecule with these nomenclatures is tentatively named nectin-like molecule-5, Necl-5.…”

Oncolytic viral therapies

“…[177][178][179][180][181][182][183] For example, poliovirus has been detargeted from nondividing neuronal cells and retargeted to replicate in malignant glioma cells by exchanging internal ribosomal entry site (IRES) elements from rhinovirus to polio. 184 The combination of a 3 0 polio UTR sequence with a 5 0 rhinovirus IRES element creates a chimeric virus that is incapable of efficient translation in neuronal cells, but is well translated in malignant cells. 1 Other studies have explored cancer and/or tissue-specific promoters that selectively control the cell site of viral replication (Table 2).…”

Nectin-like Molecule-5/Tage4 Enhances Cell Migration in an Integrin-dependent, Nectin-3-independent Manner

“…PVR/CD155 has been shown to serve as an entry receptor not only for human poliovirus but also for porcine pseudorabies virus and bovine herpesvirus 1 (29,31). PVR/CD155 is overexpressed in human colorectal carcinoma and malignant glioma (32,33). PVR/CD155 has been shown to be physically associated with CD44 on human monocyte cell surfaces (34).…”