Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Viral Transfer Technology
  • Published:

Long-term gene expression in the anterior horn motor neurons after intramuscular inoculation of a live herpes simplex virus vector

Gene Therapy volume 7, pages 934–941 (2000)Cite this article

Abstract

To clarify the feasibility of the herpes simplex virus (HSV) vector in expressing the foreign gene in the motor neuron, we inoculated a live attenuated HSV expressing β-galactosidase (β-gal) activity under a latency-associated transcript promoter in the right gastrocnemius muscle of rats. Expression of β-gal activity was observed 5 days after inoculation in the bilateral anterior horn cells of the spinal cord that innervates the inoculation muscle. However, the spread of β-gal activity was not observed in the inoculation muscle. Without significant pathological changes, the spread of β-gal-expressing neurons was observed in the lumbosacral spinal cord until 14 days after inoculation with staining concentrated in the anterior horn cells. Ninety percent of the anterior horn motor neurons expressed β-gal activity with expression continuing to at least 182 days after inoculation. Thus β-gal activity was expressed in the bilateral anterior horn cells at the lumbosacral spinal cord that innervates the inoculated muscle for a long time, possibly a life-long period. This indicates that this recombinant HSV vector system to motor neurons may further improve the understanding and treatment of neurological diseases in motor neurons of the spinal cord.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Roizman B . The function of herpes simplex virus genes: a primer for genetic engineering of novel vectors Proc Natl Acad Sci USA 1996 93: 11307–11312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Karpati G, Lochmuller H, Nalbantoglu J, Durham H . The principles of gene therapy for the nervous system Trends Neurosci 1996 19: 49–54

    Article  CAS  PubMed  Google Scholar 

  3. Fink DJ, DeLuca NA, Goins WF, Glorioso JC . Gene transfer to neurons using herpes simplex virus-based vectors Annu Rev Neurosci 1996 19: 265–287

    Article  CAS  PubMed  Google Scholar 

  4. Coffin RS, MacLean AR, Latchman DS, Brown SM . Gene delivery to the central and peripheral nervous systems of mice using HSV1 ICP34.5 deletion mutant vectors Gene Therapy 1996 3: 886–891

    CAS  PubMed  Google Scholar 

  5. Ghadge GD et al. CNS gene delivery by retrograde transport of recombinant replication-defective adenoviruses Gene Therapy 1995 2: 132–137

    CAS  PubMed  Google Scholar 

  6. Gravel C, Gotz R, Lorrain A, Sendtner M . Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons Nature Med 1997 3: 765–770

    Article  CAS  PubMed  Google Scholar 

  7. Roizman B, Sears AE . An inquiry into the mechanisms of herpes simplex virus latency Annu Rev Microbiol 1987 41: 543–571

    Article  CAS  PubMed  Google Scholar 

  8. Whitely RJ . Herpes simplex viruses. In: Fields BN et al (eds) Virology Lippincott-Raven: Philadelphia 1996 2297–2342

    Google Scholar 

  9. Stevens JG et al. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons Science 1987 235: 1056–1059

    Article  CAS  PubMed  Google Scholar 

  10. Ho DY, Mocarski ES . Beta-galactosidase as a marker in the peripheral and neural tissues of the herpes simplex virus-infected mouse Virology 1988 167: 279–283

    Article  CAS  PubMed  Google Scholar 

  11. Ho DY, Mocarski ES . Herpes simplex virus latent RNA (LAT) is not required for latent infection in the mouse Proc Natl Acad Sci USA 1989 86: 7596–7600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cook ML, Stevens JG . Pathogenesis of herpetic neuritis and ganglionitis in mice: evidence for intra-axonal transport of infection Infect Immun 1973 7: 272–288

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Keir SD, Mitchell WJ, Feldman LT, Martin JR . Targeting and gene expression in spinal cord motor neurons following intramuscular inoculation of an HSV-1 vector J Neurovirol 1995 1: 259–267

    Article  CAS  PubMed  Google Scholar 

  14. Lachmann RH, Efstathiou S . Utilization of the herpes simplex virus type 1 latency-associated regulatory region to drive stable reporter gene expression in the nervous system J Virol 1997 71: 3197–3207

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wood MJ et al. Specific patterns of defective HSV-1 gene transfer in the adult central nervous system: implications for gene targeting Exp Neurol 1994 130: 127–140

    Article  CAS  PubMed  Google Scholar 

  16. Marconi P et al. Replication-defective herpes simplex virus vectors for gene transfer in vivo Proc Natl Acad Sci USA 1996 93: 11319–11320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Neve RL, Howe JR, Hong S, Kalb RG . Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using a recombinant herpes simplex virus Neuroscience 1997 79: 435–447

    Article  CAS  PubMed  Google Scholar 

  18. Shiraki K et al. A live non-neurovirulent herpes simplex virus vector expresses beta-galactosidase in the nervous system of the Wistar and Sprague–Dawley strain rat for a prolonged period Neurosci Lett 1998 245: 69–72

    Article  CAS  PubMed  Google Scholar 

  19. Stevens JG, Cook ML . Latent herpes simplex virus in spinal ganglia of mice Science 1971 173: 843–845

    Article  CAS  PubMed  Google Scholar 

  20. Cook ML, Bastone VB, Stevens JG . Evidence that neurons harbor latent herpes simplex virus Infect Immun 1974 9: 946–951

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Rodda S, Jack I, White DO . Herpes-simplex virus from trigeminal ganglion Lancet 1973 1: 1395–1396

    Article  CAS  PubMed  Google Scholar 

  22. Warren KG et al. Isolation of Herpes simplex virus from human trigeminal ganglia, including ganglia from one patient with multiple sclerosis Lancet 1977 2: 637–639

    Article  CAS  PubMed  Google Scholar 

  23. Warren KG et al. Isolation of latent herpes simplex virus from the superior cervical and vagus ganglions of human beings New Engl J Med 1978 298: 1068–1069

    Article  CAS  PubMed  Google Scholar 

  24. Hill TJ, Blyth WA, Harbour DA . Recurrence of herpes simplex in the mouse requires an intact nerve supply to the skin J Gen Virol 1983 64: 2763–2765

    Article  PubMed  Google Scholar 

  25. Iwasaki Y et al. Eradication of herpes simplex virus persistence in rat trigeminal ganglia by retrograde axoplasmic transport J Virol 1986 59: 242–248

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kristensson K et al. Neuritic transport of herpes simplex virus in rat sensory neurons in vitro. Effects of substances interacting with microtubular function and axonal flow (nocodazole, taxol and erythro-9–3-(2-hydroxynonyl)adenine) J Gen Virol 1986 67: 2023–2028

    Article  CAS  PubMed  Google Scholar 

  27. Ugolini G . Transneuronal transfer of herpes simplex virus type 1 (HSV 1) from mixed limb nerves to the CNS. I. Sequence of transfer from sensory, motor, and sympathetic nerve fibres to the spinal cord J Comp Neurol 1992 326: 527–548

    Article  CAS  PubMed  Google Scholar 

  28. Grafstein B, Forman DS . Intracellular transport in neurons Physiol Rev 1980 60: 1167–1283

    Article  CAS  PubMed  Google Scholar 

  29. Vallee RB, Bloom GS . Mechanisms of fast and slow axonal transport Annu Rev Neurosci 1991 14: 59–92

    Article  CAS  PubMed  Google Scholar 

  30. Maratou E, Theophilidis G, Arsenakis M . Axonal transport of herpes simplex virus-1 in an in vitro model based on the isolated sciatic nerve of the frog Rana ridibunda J Neurosci Meth 1998 79: 75–78

    Article  CAS  Google Scholar 

  31. Ugolini G, Kuypers HG, Simmons A . Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV 1) from motoneurones Brain Res 1987 422: 242–256

    Article  CAS  PubMed  Google Scholar 

  32. Akli S et al. Transfer of a foreign gene into the brain using adenovirus vectors Nat Genet 1993 3: 224–328

    Article  CAS  PubMed  Google Scholar 

  33. Engelhardt JF, Ye X, Doranz B, Wilson JM . Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver Proc Natl Acad Sci USA 1994 91: 6196–6200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yang Y et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy Proc Natl Acad Sci USA 1994 91: 4407–4411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McMenamin MM et al. A gamma34.5 mutant of herpes simplex 1 causes severe inflammation in the brain Neuroscience 1998 83: 1225–1237

    Article  CAS  PubMed  Google Scholar 

  36. Deng HX et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase Science 1993 261: 1047–1051

    Article  CAS  PubMed  Google Scholar 

  37. Rosen DR . Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis Nature 1993 362: 59–62

    Article  CAS  PubMed  Google Scholar 

  38. Bowling AC, Schulz JB, Brown RH Jr, Beal MF . Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis J Neurochem 1993 61: 2322–2325

    Article  CAS  PubMed  Google Scholar 

  39. Engel WK, Kurland WK, Klatzo I . An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement: an intermediate form? Brain 1959 82: 203–220

    Article  CAS  PubMed  Google Scholar 

  40. Shiraki K et al. Caffeine inhibits paresthesia induced by herpes simplex virus through action on primary sensory neurons in rats Neurosci Lett 1998 31: 235–240

    CAS  Google Scholar 

  41. Lin H et al. Expression of recombinant genes in myocardium in vivo after direct injection of DNA Circulation 1990 82: 2217–2221

    Article  CAS  PubMed  Google Scholar 

  42. Sawtell NM, Thompson RL . Herpes simplex virus type 1 latency-associated transcription unit promotes anatomical site-dependent establishment and reactivation from latency J Virol 1992 66: 2157–2169

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank Ms Jacqueline K Brown for her editorial assistance.

Author information

Authors and Affiliations

  1. Department of Virology, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan

    J Yamamura, S Kageyama, M Kurokawa & K Shiraki

  2. Department of Physiology, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan

    T Uwano

  3. Department of Pathology, Rinku General Medical Center, Izumisano, Osaka, Japan

    M Imakita

Authors
  1. J Yamamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Kageyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Uwano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Kurokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Imakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Shiraki
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamamura, J., Kageyama, S., Uwano, T. et al. Long-term gene expression in the anterior horn motor neurons after intramuscular inoculation of a live herpes simplex virus vector. Gene Ther 7, 934–941 (2000). https://doi.org/10.1038/sj.gt.3301185

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301185

Keywords

This article is cited by

Search

Advanced search

Quick links