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Volume 96, Issue 8

An investigation of herpes simplex virus type 1 latency in a novel mouse dorsal root ganglion model suggests a role for ICP34.5 in reactivation Free

Abstract

After a primary lytic infection at the epithelia, herpes simplex virus type 1 (HSV-1) enters the innervating sensory neurons and translocates to the nucleus, where it establishes a quiescent latent infection. Periodically, the virus can reactivate and the progeny viruses spread back to the epithelium. Here, we introduce an embryonic mouse dorsal root ganglion (DRG) culture system, which can be used to study the mechanisms that control the establishment, maintenance and reactivation from latency. Use of acyclovir is not necessary in our model. We examined different phases of the HSV-1 life cycle in DRG neurons, and showed that WT HSV-1 could establish both lytic and latent form of infection in the cells. After reactivating stimulus, the WT viruses showed all markers of true reactivation. In addition, we showed that deletion of the γ34.5 gene rendered the virus incapable of reactivation, even though the virus was clearly able to replicate and persist in a quiescent form in the DRG neurons.

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© 2015 The Authors
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2015-08-01
2024-04-19
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References

  1. Arthur J.L., Scarpini C.G., Connor V., Lachmann R.H., Tolkovsky A.M., Efstathiou S. 2001; Herpes simplex virus type 1 promoter activity during latency establishment, maintenance, and reactivation in primary dorsal root neurons in vitro . J Virol 75:3885–3895 [View Article][PubMed]
     [Google Scholar]
  2. Bertke A.S., Swanson S.M., Chen J., Imai Y., Kinchington P.R., Margolis T.P. 2011; A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro . J Virol 85:6669–6677 [View Article][PubMed]
     [Google Scholar]
  3. Broberg E.K., Hukkanen V. 2005; Immune response to herpes simplex virus and gamma134.5 deleted HSV vectors. Curr Gene Ther 5:523–530 [View Article][PubMed]
     [Google Scholar]
  4. Broberg E.K., Nygårdas M., Salmi A.A., Hukkanen V. 2003; Low copy number detection of herpes simplex virus type 1 mRNA and mouse Th1 type cytokine mRNAs by Light Cycler quantitative real-time PCR. J Virol Methods 112:53–65 [View Article][PubMed]
     [Google Scholar]
  5. Camarena V., Kobayashi M., Kim J.Y., Roehm P., Perez R., Gardner J., Wilson A.C., Mohr I., Chao M.V. 2010; Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. Cell Host Microbe 8:320–330 [View Article][PubMed]
     [Google Scholar]
  6. Chou J., Roizman B. 1992; The gamma 1(34.5) gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells. Proc Natl Acad Sci U S A 89:3266–3270 [View Article][PubMed]
     [Google Scholar]
  7. Du T., Zhou G., Roizman B. 2011; HSV-1 gene expression from reactivated ganglia is disordered and concurrent with suppression of latency-associated transcript and miRNAs. Proc Natl Acad Sci U S A 108:18820–18824 [View Article][PubMed]
     [Google Scholar]
  8. Flores O., Nakayama S., Whisnant A.W., Javanbakht H., Cullen B.R., Bloom D.C. 2013; Mutational inactivation of herpes simplex virus 1 microRNAs identifies viral mRNA targets and reveals phenotypic effects in culture. J Virol 87:6589–6603 [View Article][PubMed]
     [Google Scholar]
  9. Hafezi W., Lorentzen E.U., Eing B.R., Müller M., King N.J., Klupp B., Mettenleiter T.C., Kühn J.E. 2012; Entry of herpes simplex virus type 1 (HSV-1) into the distal axons of trigeminal neurons favors the onset of nonproductive, silent infection. PLoS Pathog 8:e1002679 [View Article][PubMed]
     [Google Scholar]
  10. Honess R.W., Roizman B. 1974; Regulation of herpesvirus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. J Virol 14:8–19[PubMed]
     [Google Scholar]
  11. Hukkanen V., Rehn T., Kajander R., Sjöroos M., Waris M. 2000; Time-resolved fluorometry PCR assay for rapid detection of herpes simplex virus in cerebrospinal fluid. J Clin Microbiol 38:3214–3218[PubMed]
     [Google Scholar]
  12. Jin H., Yan Z., Ma Y., Cao Y., He B. 2011; A herpesvirus virulence factor inhibits dendritic cell maturation through protein phosphatase 1 and Ikappa B kinase. J Virol 85:3397–3407 [View Article][PubMed]
     [Google Scholar]
  13. Jurak I., Kramer M.F., Mellor J.C., van Lint A.L., Roth F.P., Knipe D.M., Coen D.M. 2010; Numerous conserved and divergent microRNAs expressed by herpes simplex viruses 1 and 2. J Virol 84:4659–4672 [View Article][PubMed]
     [Google Scholar]
  14. Kim J.Y., Mandarino A., Chao M.V., Mohr I., Wilson A.C. 2012; Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons. PLoS Pathog 8:e1002540 [View Article][PubMed]
     [Google Scholar]
  15. Kim J.Y., Shiflett L.A., Linderman J.A., Mohr I., Wilson A.C. 2014; Using homogeneous primary neuron cultures to study fundamental aspects of HSV-1 latency and reactivation. Methods Mol Biol 1144:167–179 [View Article][PubMed]
     [Google Scholar]
  16. Kobayashi M., Wilson A.C., Chao M.V., Mohr I. 2012a; Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor. Genes Dev 26:1527–1532 [View Article][PubMed]
     [Google Scholar]
  17. Kobayashi M., Kim J.Y., Camarena V., Roehm P.C., Chao M.V., Wilson A.C., Mohr I. 2012b; A primary neuron culture system for the study of herpes simplex virus latency and reactivation. J Vis Exp(62)e3823 [View Article][PubMed]
     [Google Scholar]
  18. Kristie T.M., LeBowitz J.H., Sharp P.A. 1989; The octamer-binding proteins form multi-protein–DNA complexes with the HSV alpha TIF regulatory protein. EMBO J 8:4229–4238[PubMed]
     [Google Scholar]
  19. Li Y., Zhang C., Chen X., Yu J., Wang Y., Yang Y., Du M., Jin H., Ma Y., other authors. 2011; ICP34.5 protein of herpes simplex virus facilitates the initiation of protein translation by bridging eukaryotic initiation factor 2α (eIF2α) and protein phosphatase 1. J Biol Chem 286:24785–24792 [View Article][PubMed]
     [Google Scholar]
  20. Mohr I., Sternberg D., Ward S., Leib D., Mulvey M., Gluzman Y. 2001; A herpes simplex virus type 1 γ34.5 second-site suppressor mutant that exhibits enhanced growth in cultured glioblastoma cells is severely attenuated in animals. J Virol 75:5189–5196 [View Article][PubMed]
     [Google Scholar]
  21. Nygårdas M., Paavilainen H., Müther N., Nagel C.H., Röyttä M., Sodeik B., Hukkanen V. 2013; A herpes simplex virus-derived replicative vector expressing LIF limits experimental demyelinating disease and modulates autoimmunity. PLoS One 8:e64200 [View Article][PubMed]
     [Google Scholar]
  22. Orvedahl A., Levine B. 2008; Autophagy and viral neurovirulence. Cell Microbiol 10:1747–1756 [View Article][PubMed]
     [Google Scholar]
  23. Orvedahl A., Alexander D., Tallóczy Z., Sun Q., Wei Y., Zhang W., Burns D., Leib D.A., Levine B. 2007; HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1:23–35 [View Article][PubMed]
     [Google Scholar]
  24. Paavilainen H., Romanovskaya A., Nygårdas M., Bamford D.H., Poranen M.M., Hukkanen V. 2015; Innate responses to small interfering RNA pools inhibiting herpes simplex virus infection in astrocytoid and epithelial cells. Innate Immun 21:349–357 [View Article][PubMed]
     [Google Scholar]
  25. Päiväläinen S., Nissinen M., Honkanen H., Lahti O., Kangas S.M., Peltonen J., Peltonen S., Heape A.M. 2008; Myelination in mouse dorsal root ganglion/Schwann cell cocultures. Mol Cell Neurosci 37:568–578 [View Article][PubMed]
     [Google Scholar]
  26. Perng G.C., Jones C. 2010; Towards an understanding of the herpes simplex virus type 1 latency–reactivation cycle. Interdiscip Perspect Infect Dis 2010:262415[PubMed]
     [Google Scholar]
  27. Proença J.T., Coleman H.M., Nicoll M.P., Connor V., Preston C.M., Arthur J., Efstathiou S. 2011; An investigation of herpes simplex virus promoter activity compatible with latency establishment reveals VP16-independent activation of immediate-early promoters in sensory neurones. J Gen Virol 92:2575–2585 [View Article][PubMed]
     [Google Scholar]
  28. Roizman B., Whitley R.J. 2013; An inquiry into the molecular basis of HSV latency and reactivation. Annu Rev Microbiol 67:355–374 [View Article][PubMed]
     [Google Scholar]
  29. Roizman B., Knipe D.M., Whitley R.J. 2007; Herpes simplex viruses. In Fields Virology, 5th edn. pp. 2501–2601 Edited by Knipe D. M., Howley P. M., Griffin D. E., Lamb R. A., Martin M. A., Roizman B., Straus S. E. Philadelphia, PA: Lippincott, Williams & Wilkins;
     [Google Scholar]
  30. Romanovskaya A., Paavilainen H., Nygårdas M., Bamford D.H., Hukkanen V., Poranen M.M. 2012; Enzymatically produced pools of canonical and Dicer-substrate siRNA molecules display comparable gene silencing and antiviral activities against herpes simplex virus. PLoS One 7:e51019 [View Article][PubMed]
     [Google Scholar]
  31. Sawtell N.M. 1998; The probability of in vivo reactivation of herpes simplex virus type 1 increases with the number of latently infected neurons in the ganglia. J Virol 72:6888–6892[PubMed]
     [Google Scholar]
  32. Shi T.-J.S., Tandrup T., Bergman E., Xu Z.-Q.D., Ulfhake B., Hökfelt T. 2001; Effect of peripheral nerve injury on dorsal root ganglion neurons in the C57 BL/6J mouse: marked changes both in cell numbers and neuropeptide expression. Neuroscience 105:249–263 [View Article][PubMed]
     [Google Scholar]
  33. Snijder B., Sacher R., Rämö P., Liberali P., Mench K., Wolfrum N., Burleigh L., Scott C.C., Verheije M.H., other authors. 2012; Single-cell analysis of population context advances RNAi screening at multiple levels. Mol Syst Biol 8:579 [View Article][PubMed]
     [Google Scholar]
  34. Stevens J.G., Cook M.L. 1971; Latent herpes simplex virus in spinal ganglia of mice. Science 173:843–845 [View Article][PubMed]
     [Google Scholar]
  35. Stinski M.F., Isomura H. 2008; Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency. Med Microbiol Immunol (Berl) 197:223–231 [View Article][PubMed]
     [Google Scholar]
  36. Svennerholm B., Vahlne A., Lycke E. 1981; Persistent reactivable latent herpes simplex virus infection in trigeminal ganglia of mice treated with antiviral drugs. Arch Virol 69:43–48 [View Article][PubMed]
     [Google Scholar]
  37. Tang S., Guo N., Patel A., Krause P.R. 2013; Herpes simplex virus 2 expresses a novel form of ICP34.5, a major viral neurovirulence factor, through regulated alternative splicing. J Virol 87:5820–5830 [View Article][PubMed]
     [Google Scholar]
  38. Umbach J.L., Kramer M.F., Jurak I., Karnowski H.W., Coen D.M., Cullen B.R. 2008; MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 454:780–783[PubMed]
     [Google Scholar]
  39. Verpooten D., Ma Y., Hou S., Yan Z., He B. 2009; Control of TANK-binding kinase 1-mediated signaling by the γ134.5 protein of herpes simplex virus 1. J Biol Chem 284:1097–1105 [View Article][PubMed]
     [Google Scholar]
  40. Webre J.M., Hill J.M., Nolan N.M., Clement C., McFerrin H.E., Bhattacharjee P.S., Hsia V., Neumann D.M., Foster T.P., other authors. 2012; Rabbit and mouse models of HSV-1 latency, reactivation, and recurrent eye diseases. J Biomed Biotechnol 2012:612316 [View Article][PubMed]
     [Google Scholar]
  41. Wilcox C.L., Johnson E.M. Jr 1988; Characterization of nerve growth factor-dependent herpes simplex virus latency in neurons in vitro . J Virol 62:393–399[PubMed]
     [Google Scholar]
  42. Wilson A.C., Mohr I. 2012; A cultured affair: HSV latency and reactivation in neurons. Trends Microbiol 20:604–611 [View Article][PubMed]
     [Google Scholar]
  43. Zhang M., Covar J., Zhang N.Y., Chen W., Marshall B., Mo J., Atherton S.S. 2013; Virus spread and immune response following anterior chamber inoculation of HSV-1 lacking the Beclin-binding domain (BBD). J Neuroimmunol 260:82–91 [View Article][PubMed]
     [Google Scholar]
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An investigation of herpes simplex virus type 1 latency in a novel mouse dorsal root ganglion model suggests a role for ICP34.5 in reactivation
J. Gen. Virol. 96, 2304 (2015); https://doi.org/10.1099/vir.0.000138
/content/journal/jgv/10.1099/vir.0.000138
/content/journal/jgv/10.1099/vir.0.000138
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