Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. “Oncolytic” viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Gromeier M, Alexander L, Wimmer E. 1.  1996. Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants. PNAS 93:2370–75 [Google Scholar]
  2. Dobrikova EY, Goetz C, Walters RW. 2.  et al. 2012. Attenuation of neurovirulence, biodistribution, and shedding of a poliovirus:rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis. J. Virol. 86:2750–59 [Google Scholar]
  3. Desjardins A, Sampson JH, Peters K. 3.  et al. 2013. Phase I study of an oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma. Proc. SNO Annual Meeting107 San Francisco: Soc. Neuro-Oncol. [Google Scholar]
  4. Takai Y, Miyoshi J, Ikeda W, Ogita H. 4.  2008. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat. Rev. Mol. Cell Biol. 9:603–15 [Google Scholar]
  5. Brown MC, Gromeier M. 5.  2015. Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus. Curr. Opin. Virol. 13:81–85 [Google Scholar]
  6. Holl EK, Brown MC, Boczkowski D. 6.  et al. 2016. Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models. Oncotarget 7:79828–41 [Google Scholar]
  7. Bodian D. 7.  1955. Emerging concept of poliomyelitis infection. Science 122:105–8 [Google Scholar]
  8. Sabin AB. 8.  1956. Pathogenesis of poliomyelitis; reappraisal in the light of new data. Science 123:1151–57 [Google Scholar]
  9. Chandramohan V, Bryant J, Piao H. 9.  et al. 2017. Validation of an immunohistochemistry assay for detection of CD155, the poliovirus receptor, in malignant gliomas. Arch. Pathol. Lab. Med. In press. doi: 10.5858/arpa.2016-0580-OA
  10. Iwasaki A, Welker R, Mueller S. 10.  et al. 2002. Immunofluorescence analysis of poliovirus receptor expression in Peyer's patches of humans, primates, and CD155 transgenic mice: implications for poliovirus infection. J. Infect. Dis. 186:585–92 [Google Scholar]
  11. Sabin AB, Boulger LR. 11.  1973. History of Sabin attenuated poliovirus oral live vaccine strains. J. Biol. Stand. 1:115–18 [Google Scholar]
  12. Sabin AB. 12.  1957. Properties and behavior of orally administered attenuated poliovirus vaccine. JAMA 164:1216–23 [Google Scholar]
  13. Wimmer E, Hellen CU, Cao X. 13.  1993. Genetics of poliovirus. Annu. Rev. Genet. 27:353–436 [Google Scholar]
  14. Evans DM, Dunn G, Minor PD. 14.  et al. 1985. Increased neurovirulence associated with a single nucleotide change in a noncoding region of the Sabin type 3 poliovaccine genome. Nature 314:548–50 [Google Scholar]
  15. Georgescu MM, Balanant J, Macadam A. 15.  et al. 1997. Evolution of the Sabin type 1 poliovirus in humans: characterization of strains isolated from patients with vaccine-associated paralytic poliomyelitis. J. Virol. 71:7758–68 [Google Scholar]
  16. Jang SK, Krausslich HG, Nicklin MJ. 16.  et al. 1988. A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J. Virol. 62:2636–43 [Google Scholar]
  17. Pelletier J, Sonenberg N. 17.  1988. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334:320–25 [Google Scholar]
  18. de Breyne S, Yu Y, Unbehaun A. 18.  et al. 2009. Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites. PNAS 106:9197–202 [Google Scholar]
  19. Sweeney TR, Abaeva IS, Pestova TV, Hellen CU. 19.  2014. The mechanism of translation initiation on Type 1 picornavirus IRESs. EMBO J 33:76–92 [Google Scholar]
  20. Ochs K, Zeller A, Saleh L. 20.  et al. 2003. Impaired binding of standard initiation factors mediates poliovirus translation attenuation. J. Virol. 77:115–22 [Google Scholar]
  21. Brown MC, Bryant JD, Dobrikova EY. 21.  et al. 2014. Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase. J. Virol. 88:13135–48 [Google Scholar]
  22. Brown MC, Dobrikov MI, Gromeier M. 22.  2014. Mitogen-activated protein kinase-interacting kinase regulates mTOR/AKT signaling and controls the serine/arginine-rich protein kinase-responsive type 1 internal ribosome entry site-mediated translation and viral oncolysis. J. Virol. 88:13149–60 [Google Scholar]
  23. Brown MC, Gromeier M. 23.  2015. Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus. Discov. Med. 19:359–65 [Google Scholar]
  24. Brown MC, Gromeier M. 24.  2017. MNK controls mTORC1:substrate association through regulation of TELO2 binding with mTORC1. Cell Rep 18:1444–57 [Google Scholar]
  25. Dobrikov M, Dobrikova E, Shveygert M, Gromeier M. 25.  2011. Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) by protein kinase Cα regulates eIF4G1 binding to Mnk1. Mol. Cell. Biol. 31:2947–59 [Google Scholar]
  26. Dobrikov MI, Dobrikova EY, Gromeier M. 26.  2013. Dynamic regulation of the translation initiation helicase complex by mitogenic signal transduction to eukaryotic translation initiation factor 4G. Mol. Cell. Biol. 33:937–46 [Google Scholar]
  27. Goetz C, Everson RG, Zhang LC, Gromeier M. 27.  2010. MAPK signal-integrating kinase controls cap-independent translation and cell type-specific cytotoxicity of an oncolytic poliovirus. Mol. Ther. 18:1937–46 [Google Scholar]
  28. Campbell SA, Lin J, Dobrikova EY, Gromeier M. 28.  2005. Genetic determinants of cell type-specific poliovirus propagation in HEK 293 cells. J. Virol. 79:6281–90 [Google Scholar]
  29. Dobrikova EY, Broadt T, Poiley-Nelson J. 29.  et al. 2008. Recombinant oncolytic poliovirus eliminates glioma in vivo without genetic adaptation to a pathogenic phenotype. Mol. Ther. 16:1865–72 [Google Scholar]
  30. Merrill MK, Dobrikova EY, Gromeier M. 30.  2006. Cell-type-specific repression of internal ribosome entry site activity by double-stranded RNA-binding protein 76. J. Virol. 80:3147–56 [Google Scholar]
  31. Merrill MK, Gromeier M. 31.  2006. The double-stranded RNA binding protein 76:NF45 heterodimer inhibits translation initiation at the rhinovirus type 2 internal ribosome entry site. J. Virol. 80:6936–42 [Google Scholar]
  32. Mendelsohn CL, Wimmer E, Racaniello VR. 32.  1989. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56:855–65 [Google Scholar]
  33. Kishimoto T, Kikutani H, Von dem Borne AEGK. 33.  et al. 1997. Leucocyte Typing VI: White Cell Differentiation Antigens New York: Garland
  34. Nobis P, Zibirre R, Meyer G. 34.  et al. 1985. Production of a monoclonal antibody against an epitope on HeLa cells that is the functional poliovirus binding site. J. Gen. Virol. 66:Pt. 122563–69 [Google Scholar]
  35. Khan S, Peng X, Yin J. 35.  et al. 2008. Characterization of the New World monkey homologues of human poliovirus receptor CD155. J. Virol. 82:7167–79 [Google Scholar]
  36. Freistadt MS, Eberle KE. 36.  2000. Hematopoietic cells from CD155-transgenic mice express CD155 and support poliovirus replication ex vivo. Microb. Pathog. 29:203–12 [Google Scholar]
  37. Freistadt MS, Fleit HB, Wimmer E. 37.  1993. Poliovirus receptor on human blood cells: a possible extraneural site of poliovirus replication. Virology 195:798–803 [Google Scholar]
  38. Wahid R, Cannon MJ, Chow M. 38.  2005. Dendritic cells and macrophages are productively infected by poliovirus. J. Virol. 79:401–9 [Google Scholar]
  39. Manes TD, Pober JS. 39.  2011. Identification of endothelial cell junctional proteins and lymphocyte receptors involved in transendothelial migration of human effector memory CD4+ T cells. J. Immunol. 186:1763–68 [Google Scholar]
  40. Reymond N, Imbert AM, Devilard E. 40.  et al. 2004. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199:1331–41 [Google Scholar]
  41. Ren S, Rollins BJ. 41.  2004. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 117:239–51 [Google Scholar]
  42. Blinzinger K, Simon J, Magrath D, Boulger L. 42.  1969. Poliovirus crystals within the endoplasmic reticulum of endothelial and mononuclear cells in the monkey spinal cord. Science 163:1336–37 [Google Scholar]
  43. Solecki D, Schwarz S, Wimmer E. 43.  et al. 1997. The promoters for human and monkey poliovirus receptors. Requirements for basic and cell type-specific activity. J. Biol. Chem. 272:5579–86 [Google Scholar]
  44. Erickson BM, Thompson NL, Hixson DC. 44.  2006. Tightly regulated induction of the adhesion molecule necl-5/CD155 during rat liver regeneration and acute liver injury. Hepatology 43:325–34 [Google Scholar]
  45. Cerboni C, Fionda C, Soriani A. 45.  et al. 2014. The DNA damage response: a common pathway in the regulation of NKG2D and DNAM-1 ligand expression in normal, infected, and cancer cells. Front. Immunol. 4:508 [Google Scholar]
  46. Blake SJ, Stannard K, Liu J. 46.  et al. 2016. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov 6:446–59 [Google Scholar]
  47. Chan CJ, Martinet L, Gilfillan S. 47.  et al. 2014. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat. Immunol. 15:431–38 [Google Scholar]
  48. Dougall WC, Kurtulus S, Smyth MJ, Anderson AC. 48.  2017. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol. Rev. 276:112–20 [Google Scholar]
  49. Martinet L, Smyth MJ. 49.  2015. Balancing natural killer cell activation through paired receptors. Nat. Rev. Immunol. 15:243–54 [Google Scholar]
  50. Stanietsky N, Simic H, Arapovic J. 50.  et al. 2009. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. PNAS 106:17858–63 [Google Scholar]
  51. Solecki D, Gromeier M, Harber J. 51.  et al. 1998. Poliovirus and its cellular receptor: a molecular genetic dissection of a virus/receptor affinity interaction. J. Mol. Recognit. 11:2–9 [Google Scholar]
  52. Katze MG, He Y, Gale M Jr.. 52.  2002. Viruses and interferon: a fight for supremacy. Nat. Rev. Immunol. 2:675–87 [Google Scholar]
  53. Takeuchi O, Akira S. 53.  2009. Innate immunity to virus infection. Immunol. Rev. 227:75–86 [Google Scholar]
  54. Schneider WM, Chevillotte MD, Rice CM. 54.  2014. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32:513–45 [Google Scholar]
  55. Stojdl DF, Lichty B, Knowles S. 55.  et al. 2000. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat. Med. 6:821–25 [Google Scholar]
  56. Barrett PN, Mundt W, Kistner O, Howard MK. 56.  2009. Vero cell platform in vaccine production: moving towards cell culture-based viral vaccines. Expert Rev. Vaccines 8:607–18 [Google Scholar]
  57. Desmyter J, Melnick JL, Rawls WE. 57.  1968. Defectiveness of interferon production and of rubella virus interference in a line of African green monkey kidney cells (Vero). J. Virol. 2:955–61 [Google Scholar]
  58. Osada N, Kohara A, Yamaji T. 58.  et al. 2014. The genome landscape of the African green monkey kidney-derived Vero cell line. DNA Res 21:673–83 [Google Scholar]
  59. Glas M, Coch C, Trageser D. 59.  et al. 2013. Targeting the cytosolic innate immune receptors RIG-I and MDA5 effectively counteracts cancer cell heterogeneity in glioblastoma. Stem Cells 31:1064–74 [Google Scholar]
  60. Zamarin D, Holmgaard RB, Subudhi SK. 60.  et al. 2014. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6:226ra32 [Google Scholar]
  61. Morrison JM, Racaniello VR. 61.  2009. Proteinase 2Apro is essential for enterovirus replication in type I interferon-treated cells. J. Virol. 83:4412–22 [Google Scholar]
  62. Etchison D, Milburn SC, Edery I. 62.  et al. 1982. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J. Biol. Chem. 257:14806–10 [Google Scholar]
  63. Richards OC, Martin SC, Jense HG, Ehrenfeld E. 63.  1984. Structure of poliovirus replicative intermediate RNA. Electron microscope analysis of RNA cross-linked in vivo with psoralen derivative. J. Mol. Biol. 173:325–40 [Google Scholar]
  64. Brown MC, Dobrikova EY, Dobrikov MI. 64.  et al. 2014. Oncolytic polio virotherapy of cancer. Cancer 120:3277–86 [Google Scholar]
  65. Kolaczkowska E, Kubes P. 65.  2013. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13:159–75 [Google Scholar]
  66. Gromeier M, Lachmann S, Rosenfeld MR. 66.  et al. 2000. Intergeneric poliovirus recombinants for the treatment of malignant glioma. PNAS 97:6803–8 [Google Scholar]
  67. Pittman K, Kubes P. 67.  2013. Damage-associated molecular patterns control neutrophil recruitment. J. Innate Immun. 5:315–23 [Google Scholar]
  68. Kim ND, Luster AD. 68.  2015. The role of tissue resident cells in neutrophil recruitment. Trends Immunol 36:547–55 [Google Scholar]
  69. Fleming HE, Little FF, Schnurr D. 69.  et al. 1999. Rhinovirus-16 colds in healthy and in asthmatic subjects: similar changes in upper and lower airways. Am. J. Respir. Crit. Care Med. 160:100–8 [Google Scholar]
  70. Graham D, Henderson F, House D. 70.  1988. Neutrophil influx measured in nasal lavages of humans exposed to ozone. Arch. Environ. Health 43:228–33 [Google Scholar]
  71. Jarjour NN, Gern JE, Kelly EA. 71.  et al. 2000. The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J. Allergy Clin. Immunol. 105:1169–77 [Google Scholar]
  72. Mallia P, Message SD, Contoli M. 72.  et al. 2013. Neutrophil adhesion molecules in experimental rhinovirus infection in COPD. Respir. Res. 14:72 [Google Scholar]
  73. Naclerio RM, Proud D, Lichtenstein LM. 73.  et al. 1988. Kinins are generated during experimental rhinovirus colds. J. Infect. Dis. 157:133–42 [Google Scholar]
  74. Zhu J, Message SD, Qiu Y. 74.  et al. 2014. Airway inflammation and illness severity in response to experimental rhinovirus infection in asthma. Chest 145:1219–29 [Google Scholar]
  75. Deniset JF, Kubes P. 75.  2016. Recent advances in understanding neutrophils. F1000Res 5:2912 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error