Hypoxia Enhances the Replication of Oncolytic Herpes Simplex Virus

Aghi, Manish K.; Liu, Ta‐Chiang; Rabkin, Samuel D.; Martuza, Robert L.

doi:10.1038/mt.2008.232

Cited by 66 publications

(64 citation statements)

References 36 publications

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“…Concerning hepatocytes, low oxygen is essential for the preservation of their structure and metabolism (19). Moreover, hypoxia affects the replication of several viruses (20)(21)(22)(23)(24)(25)(26).Based on these observations, we studied the impact of oxygen tension on HCV replication and virus production in human hepatoma (Huh7) cells. We show that low oxygen selectively enhances HCV RNA replication at an early stage and in a hypoxia-inducible factor (HIF)-independent manner.…”

mentioning

confidence: 99%

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Vassilaki

Kalliampakou

Kotta‐Loizou

et al. 2013

J Virol

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; Applied Molecular Virology, Institut Pasteur Korea, Seongnam-si, South Korea g Low oxygen tension exerts a significant effect on the replication of several DNA and RNA viruses in cultured cells. In vitro propagation of hepatitis C virus (HCV) has thus far been studied under atmospheric oxygen levels despite the fact that the liver tissue microenvironment is hypoxic. In this study, we investigated the efficiency of HCV production in actively dividing or differentiating human hepatoma cells cultured under low or atmospheric oxygen tensions. By using both HCV replicons and infectionbased assays, low oxygen was found to enhance HCV RNA replication whereas virus entry and RNA translation were not affected. Hypoxia signaling pathway-focused DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR) analyses revealed an upregulation of genes related to hypoxic stress, glycolytic metabolism, cell growth, and proliferation when cells were kept under low (3% [vol/vol]) oxygen tension, likely reflecting cell adaptation to anaerobic conditions. Interestingly, hypoxia-mediated enhancement of HCV replication correlated directly with the increase in anaerobic glycolysis and creatine kinase B (CKB) activity that leads to elevated ATP production. Surprisingly, activation of hypoxia-inducible factor alpha (HIF-␣) was not involved in the elevation of HCV replication. Instead, a number of oncogenes known to be associated with glycolysis were upregulated and evidence that these oncogenes contribute to hypoxia-mediated enhancement of HCV replication was obtained. Finally, in liver biopsy specimens of HCV-infected patients, the levels of hypoxia and anaerobic metabolism markers correlated with HCV RNA levels. These results provide new insights into the impact of oxygen tension on the intricate HCVhost cell interaction. H epatitis C virus (HCV) infection causes a wide range of clinical manifestations, from a healthy carrier state to acute and chronic hepatitis that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Nearly 3% of the world's population is chronically infected with HCV (1, 2), and current therapeutic approaches are not broadly effective (3).HCV is a positive-strand RNA virus with a 9.6-kb genome that is flanked at both termini by conserved, nontranslated regions (NTRs), required for RNA translation and replication. The 5= NTR comprises an internal ribosome entry site (IRES) that directs the expression of a polyprotein precursor (4, 5). The polyprotein is cleaved into structural (core, E1, E2) and nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins that, in association with cellular factors, form a membrane-associated replicase complex. This copies the viral positive-strand RNA into a negative-strand intermediate that serves as the template for the synthesis of progeny genomes. The alternative reading frame (ARFP) or coreϩ1 and minicore proteins, with as-yet-unknown functions, appear to be synthesized from the core region by alternative translation mechanisms (6, 7).Studies of the...

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mentioning

confidence: 99%

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Vassilaki

Kalliampakou

Kotta‐Loizou

et al. 2013

J Virol

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“…One hallmark of GBM is the presence of a hypoxic microenvironment, which has been shown to maintain GSC stemness. 54 In contrast to other therapies, G207 replicated better in glioma cell lines in vitro under hypoxic compared with normoxic conditions, 55 while G47Δ replicated similarly in hypoxic and nonhypoxic regions of GSC-derived tumors. 56 …”

Section: Cytotoxic Gene Therapy Oncolytic Viruses Herpes Simplex Virusmentioning

confidence: 98%

Current Status of Gene Therapy for Brain Tumors∗

Ning

Rabkin

2015

Translating Gene Therapy to the Clinic

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Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replicationcompetent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.Treating malignant gliomas, of which glioblastoma (GBM) is the most common and least curable, remains a daunting challenge even after substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiation and temozolomide chemotherapy; however, the median survival still remains less than 15 months. 1,2 This poor survival is due to the aggressive and invasive nature of the tumor cells, resistance to treatment, and the challenges of delivering therapeutics into the brain. 3 GBM is thought to be derived from a small population of glioblastoma stem cells (GSCs), so-called because of their stem cell-like properties of self-renewal and multilineage differentiation while being highly tumorigenic. [4][5][6] GSCs have become an important model for studying GBM because their xenografts mimic the heterogeneous histopathology of the patient's tumor from which they were derived 7,8 and they remain genotypically similar to the patient's tumor, in contrast to serum-cultured cell lines. 9 These cells have provided insights into the origin of tumor-initiating cells and new targets for therapy. Other GBM animal models include established glioma cell lines (human and rodent) implanted intracranially into immunodeficient or immunocompetent animals, and genetically engineered mice that spontaneously develop brain tumors or are induced with viral vectors. 10 GENE DELIVERY VEHICLES FOR GLIOBLASTOMAMost gene therapies for GBM use biologic vectors such as viruses or cells. Replicationdefective or non-repli...

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“…It has been reported that oncolytic HSV-1 replicates preferentially in the hypoxic environment. 20) We constructed a fusion protein between amino terminal region of ICP4, a transcription factor essential for viral replication, and a 56 amino-acid sequence regulating oxygen-dependent protein degradation of HIF1a. In this oncolytic HSV-1, ICP4 protein is degraded in the normoxic condition and is expressed in the hypoxic condition.…”

Section: Fig 3b Expression Of Calponin 1 In Mesothelioma Cellsmentioning

confidence: 99%

Development of Incurable Cancer Cell Targeted Agents Using Viral Technology

Yamamura

Takahashi

2013

YAKUGAKU ZASSHI

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The safety and anti-tumor eŠect of oncolytic virus have been reported in a clinical study conducted in Japan. We have engineered a novel multimutated tumor-speciˆc oncolytic herpes virus, harboring a smooth muscle-speciˆc calponin promoter. Since tumor cells present in a hypoxic environment are known to be resistant to chemotherapy and radiotherapy, we also engineered a novel oncolytic herpes virus targeting a speciˆc tumor microenvironment, which harbors a gene encoding a fusion protein of oxygen-dependent degradation (ODD) domain of HIF1a and ICP4, a master viral transcription factor required for replication. The recombinant virus selectively replicates in and disrupts the target tumor cells, including human sarcoma and malignant mesothelioma cells which are unresponsive to chemotherapy and molecular targeted therapy. We conˆrmed signiˆcant anti-tumor eŠects of the novel viruses in vivo in an allogeneic experimental model of an undiŠerentiated pleomorphic sarcoma (malignantˆbrous histiocytoma; MFH) spontaneously generated in immunocompetent Fischer rats. Our viruses, manufactured in the Master Virus Seed Stock in the Good Manufacturing Practice facility will become novel agents that enable tumor cells unresponsive to conventional treatment to be disrupted.

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Hypoxia Enhances the Replication of Oncolytic Herpes Simplex Virus

Cited by 66 publications

References 36 publications

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Current Status of Gene Therapy for Brain Tumors∗

Development of Incurable Cancer Cell Targeted Agents Using Viral Technology

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