Abstract
The authors have recently demonstrated that wild-type myxoma virus (MV) tagged with gfp (vMyxgfp) can generate a tumor-specific infection that productively infects and clears human tumor-derived xenografts when injected intratumorly into human gliomas transplanted into immunodeficient mice (Lun et al, 2005). To expand the understanding of MV tropism in cancer cells from a specific tissue lineage, the authors have screened a series of human glioma cells (U87, U118, U251, U343, U373) for myxoma virus replication and oncolysis. To assess the viral tropism determinants for these infections, the authors have screened myxoma virus knockout constructs that have been deleted for specific host range genes (M-T2, M-T4, M-T5, M11L, and M063), as well as a control MV gene knockout construct with no known host range function (vMyx135KO) but is highly attenuated in rabbits. The authors report wide variation in the ability of various vMyx-hrKOs to replicate and spread in the human glioma cells as measured by early and late viral gene expression. This differential ability to support vMyx-hrKO productive viral replication is consistent with levels of endogenous activated Akt in the various gliomas. The authors have identified one vMyx-hrKO virus (vMyx63KO) and one nonhost range knock-out construct (vMyx135KO) that appear to replicate in the gliomas even more efficiently than the wild-type virus and that reduce the viability of the infected gliomas. These knockout viruses also inhibit the proliferation of gliomas in a manner similar to the wild-type virus. Together these data, as well as the fact that these knockout viruses are attenuated in their natural hosts, may represent environmentally safer candidate oncolytic viruses for usage in human trials.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barrett JW, Shun Chang C, Wang G, Werden SJ, Shao Z, Barrett C, Gao X, Belsito TA, Villenevue D, McFadden G (2007a). Myxoma virus M063R is a host range gene essential for virus replication in rabbit cells. Virology 361: 123–132.
Barrett JW, Sypula J, Wang F, Alston LR, Shao Z, Gao X, Irvine TS, McFadden G (2007b). M135R is a novel cell surface virulence factor of myxoma virus. J Virol 81: 106–114.
Barry M, Hnatiuk S, Mossman K, Lee SF, Boshkov L, McFadden G (1997). The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is retained within the endoplasmic reticulum and is important for the productive infection of lymphocytes. Virology 239: 360–377.
Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C (2006). Clonogenic assay of cells in vitro. Nat Protoc 1: 2315–2319.
Gaddy DF, Lyles DS (2007). Oncolytic vesicular stomatitis virus induces apoptosis via signaling through PKR, Fas, and Daxx. J Virol 81: 2792–2804.
Hill C, Hunter SB, Brat DJ (2003). Genetic markers in glioblastoma: prognostic significance and future therapeutic implications. Adv Anat Pathol 10: 212–217.
Hnatiuk S, Barry M, Zeng W, Liu L, Lucas A, Percy D, McFadden G (1999). Role of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and viral pathogenesis. Virology 263: 290–306.
Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC, Van Meir EG (1999). Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9: 469–479.
Johnston JB, McFadden G (2004). Technical knockout: understanding poxvirus pathogenesis by selectively deleting viral immunomodulatory genes. Cell Microbiol 9: 695–705.
King GD, Curtin JF, Candolfi M, Kroeger K, Lowenstein PR, Castro MG (2005). Gene therapy and targeted toxins for glioma. Curr Gene Ther 5: 535–557.
Knobbe CB, Trampe-Kieslich A, Reifenberger G (2005). Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol Appl Neurobiol 31: 486–490.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947.
Liu TC, Galanis E, Kirn D (2007). Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol 4: 101–117.
Liu TC, Kirn D (2007). Systemic efficacy with oncolytic virus therapeutics: clinical proof-of-concept and future directions. Cancer Res 67: 429–432.
Lun X, Yang W, Alain T, Shi Z-Q, Muzik H, Barrett JW, McFadden G, Bell J, Hamilton MG, Senger DL, Forsyth PA (2005). Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas. Cancer Res 65: 9982–9990.
Macen JL, Graham KA, Lee SF, Schreiber M, Boshkov LK, McFadden G (1996). Expression of the myxoma virus tumor necrosis factor receptor homologue (T2) and M11L genes is required to prevent virus-induced apoptosis in infected rabbit T lymphocytes. Virology 218: 232–237.
Macen JL, Upton C, Nation N, McFadden G (1993). SERP1, a serine proteinase inhibitor encoded by myxoma virus, is a secreted glycoprotein that interferes with inflammation. Virology 195: 348–363.
McFadden G (2005). Poxvirus Tropism. Nature Reviews Microbiology 3: 201–213.
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005). Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353: 2012–2024.
Merrill MK, Selznick LA, Gromeier M (2006). Oncolytic viruses fro the treatment of malignant glioma. Expert Opin Ther Patents 16: 363–371.
Mossman K, Lee SF, Barry M, Boshkov L, McFadden G (1996). Disruption of M-T5, a novel myxoma virus gene member of poxvirus host range superfamily, results in dramatic attenuation of myxomatosis in infected European rabbits. J Virol 70: 4394–4410.
Nash P, Barry M, Seet BT, Veugelers K, Hota S, Heger J, Hodgkinson C, Graham K, Jackson RJ, McFadden G (2000). Post-translational modification of the myxomavirus anti-inflammatory serpin SERP-1 by a virally encoded sialyltransferase. Biochem J 347: 375–382.
Opgenorth A, Graham K, Nation N, Strayer D, McFadden G (1992). Deletion analysis of two tandemly arranged virulence genes in myxoma virus, M11L and myxoma growth factor. J Virol 66: 4720–4731.
Parato KA, Senger D, Forsyth PA, Bell JC (2005). Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 5: 965–976.
Rao RD, James CD (2004). Altered molecular pathways in gliomas: an overview of clinically relevant issues. Semin Oncol 31: 595–604.
Roberts MS, Lorence RM, Groene WS, Bamat MK (2006). Naturally oncolytic viruses. Curr Opin Mol Ther 8: 314–321.
Schreiber M, Sedger L, McFadden G (1997). Distinct domains of M-T2, the myxoma virus TNF receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition. J Virol 71: 2171–2181.
Stanford MM, Barrett JW, Nazarian SH, Werden S, McFadden G (2007). Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells. J Virol 81: 1251–1260.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362.
Stojdl DF, Lichty BD, tenOever BR, Paterson JM, Power AT, Knowles S, Marius R, Reynard J, Poliquin L, Atkins H, Brown EG, Durbin RK, Durbin JE, Hiscott J, Bell JC (2003). VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4: 263–275.
Sypula J, Wang F, Ma Y, Bell J, McFadden G (2004). Myxoma virus tropism in human tumor cells. Gene Ther Mol Biol 8: 103–114.
Tong A (2006). Oncolytic viral therapy for human cancer: challenges revisited. Drug Dev Res 66: 260–277.
Upton C, Macen JL, Schreiber M, McFadden G (1991). Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence. Virology 184: 370–382.
Upton C, Mossman K, McFadden G (1992). Encoding of a homolog of the IFN-gamma receptor by myxoma virus. Science 258: 1369–1372.
Wang G, Barrett JW, Stanford M, Werden SJ, Johnston JB, Gao X, Sun M, Cheng JQ, McFadden G (2006). Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. Proc Natl Acad Sci U S A 103: 4640–4645.
Werden SJ, Barrett JW, Wang G, Stanford MM, McFadden G (2007). M-T5, the ankyrin repeat, host range protein of myxoma virus, activates Akt and can be functionally replaced by cellular PIKE-A. J Virol 81: 2340–2348.
Wollmann G, Robek MD, van den Pol AN (2007). Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells. J Virol 81: 1479–1491.
Wollmann G, Tattersall P, van den Pol AN (2005). Targeting human glioblastoma cells: comparison of nine viruses with oncolytic potential. J Virol 79: 6005–6022.
Woo Y, Adusumilli PS, Fong Y (2006). Advances in oncolytic viral therapy. Curr Opin Investig Drugs 7: 549–559.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by grants from the National Cancer Institute of Canada, the Terry Fox Foundation (GM and PF) and the Canadian Institutes of Health Research. GM is an International Scholar of The Howard Hughes Medical Institute.
Rights and permissions
About this article
Cite this article
Barrett, J.W., Alston, L.R., Wang, F. et al. Identification of host range mutants of myxoma virus with altered oncolytic potential in human glioma cells. Journal of NeuroVirology 13, 549–560 (2007). https://doi.org/10.1080/13550280701591526
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1080/13550280701591526