Skip to main content

Advertisement

SpringerLink
Log in

Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia

  • Short Communication
  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Varicella zoster virus (VZV), a human neurotropic alphaherpesvirus, becomes latent after primary infection and reactivates to produce zoster. To study VZV latency and reactivation, human trigeminal ganglia removed within 24 h after death were mechanically dissociated, randomly distributed into six-well tissue culture plates and incubated with reagents to inactivate nerve growth factor (NGF) or phosphoinositide 3-kinase (PI3-kinase) pathways. At 5 days, VZV DNA increased in control and PI3-kinase inhibitor-treated cultures to the same extent, but was significantly more abundant in anti-NGF-treated cultures (p = 0.001). Overall, VZV DNA replication is regulated in part by an NGF pathway that is PI3-kinase-independent.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  • Azarkh Y, Bos N, Gilden D, Cohrs RJ (2012) Human trigeminal ganglionic explants as a model to study alphaherpesvirus reactivation. J Neurovirol 18:456–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Camarena V, Kobayashi M, Kim JY, Roehm P, Perez R, Gardner J, Wilson AC, Mohr I, Chao MV (2010) Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. Cell Host Microbe 8:320–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carton C, Kilbourne ED (1952) Activation of latent herpes simplex by trigeminal sensory-root section. N Engl J Med 246:172–176

    Article  CAS  PubMed  Google Scholar 

  • Clarke P, Beer T, Cohrs R, Gilden DH (1995) Configuration of latent varicella-zoster virus DNA. J Virol 69:8151–8154

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cohrs RJ, Gilden DH (2007) Prevalence and abundance of latently transcribed varicella-zoster virus genes in human ganglia. J Virol 81:2950–2956

    Article  CAS  PubMed  Google Scholar 

  • Cohrs RJ, Randall J, Smith J, Gilden DH, Dabrowski C, van Der KH, Tal-Singer R (2000) Analysis of individual human trigeminal ganglia for latent herpes simplex virus type 1 and varicella-zoster virus nucleic acids using real-time PCR. J Virol 74:11464–11471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohrs RJ, Laguardia JJ, Gilden D (2005) Distribution of latent herpes simplex virus type-1 and varicella zoster virus DNA in human trigeminal ganglia. Virus Genes 31:223–227

    Article  CAS  PubMed  Google Scholar 

  • Cohrs RJ, Badani H, Bos N, Scianna C, Hoskins I, Baird NL, Gilden D (2016) Alphaherpesvirus DNA replication in dissociated human trigeminal ganglia. J Neurovirol, in press; doi:10.1007/s13365-016-0450-7

  • Cushing H (1905) Surgical aspects of major neuralgia of trigeminal nerve: report of 20 cases of operation upon the Gasserian ganglion with anatomic and physiologic notes on the consequences of its removal. J Am Med Assoc 44:3773–3379

    Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du T, Zhou G, Roizman B (2013) Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3. Proc Natl Acad Sci U S A 110:E2621–E2628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du T, Han Z, Zhou G, Roizman B (2015) Patterns of accumulation of miRNAs encoded by herpes simplex virus during productive infection, latency, and on reactivation. Proc Natl Acad Sci U S A 112:E49–E55

    Article  CAS  PubMed  Google Scholar 

  • Eaton HE, Saffran HA, Wu FW, Quach K, Smiley JR (2014) Herpes simplex virus protein kinases US3 and UL13 modulate VP11/12 phosphorylation, virion packaging, and phosphatidylinositol 3-kinase/Akt signaling activity. J Virol 88:7379–7388

    Article  PubMed  PubMed Central  Google Scholar 

  • Efstathiou S, Minson AC, Field HJ, Anderson JR, Wildy P (1986) Detection of herpes simplex virus-specific DNA sequences in latently infected mice and in humans. J Virol 57:446–455

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eshleman E, Shahzad A, Cohrs RJ (2011) Varicella zoster virus latency. Future Virol 6:341–355

    Article  PubMed  PubMed Central  Google Scholar 

  • Furuta Y, Ohtani F, Fukuda S, Inuyama Y, Nagashima K (2000) Reactivation of varicella-zoster virus in delayed facial palsy after dental treatment and orofacial surgery. J Med Virol 62:42–45

    Article  CAS  PubMed  Google Scholar 

  • Gershon AA, Chen J, Davis L, Krinsky C, Cowles R, Reichard R, Gershon M (2012) Latency of varicella zoster virus in dorsal root, cranial, and enteric ganglia in vaccinated children. Trans Am Clin Climatol Assoc 123:17–33

    PubMed  PubMed Central  Google Scholar 

  • Gershon AA, Breuer J, Cohen JI, Cohrs RJ, Gershon MD, Gilden D, Grose C, Hambleton S, Kennedy PG, Oxman MN, Seward JF, Yamanishi K (2015) Varicella zoster virus infection. Nat Rev Dis Primers 150(16):1–18. doi:10.1038/nrdp.2015.16

  • Gilden D (2015) Varicella-zoster virus infections. Continuum (Minneapolis, MN) 21:1692–1703

    Google Scholar 

  • Gilden DH, Vafai A, Shtram Y, Becker Y, Devlin M, Wellish M (1983) Varicella-zoster virus DNA in human sensory ganglia. Nature 306:478–480

    Article  CAS  PubMed  Google Scholar 

  • Gilden DH, Rozenman Y, Murray R, Devlin M, Vafai A (1987) Detection of varicella zoster virus nucleic acid in neurons of normal human thoracic ganglia. Ann Neurol 22:377–280

    Article  CAS  PubMed  Google Scholar 

  • Gluska S, Chein M, Rotem N, Ionescu A, Perlson E (2016) Tracking Quantum-Dot labeled neurotropic factors transport along primary neuronal axons in compartmental microfluidic chambers. Methods Cell Biol 131:365–387

    Article  PubMed  Google Scholar 

  • Grose C, Brunel PA (1978) Varicella-zoster virus: isolation and propagation in human melanoma cells at 36 and 32 degrees C. Infect Immun 19:199–203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kennedy PG, Grinfeld E, Gow JW (1998) Latent varicella-zoster virus is located predominantly in neurons in human trigeminal ganglia. Proc Natl Acad Sci U S A 95:4658–4662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kennedy PG, Grinfeld E, Gow JW (1999) Latent Varicella-zoster virus in human dorsal root ganglia. Virology 258:451–454

    Article  CAS  PubMed  Google Scholar 

  • Kennedy PG, Rovnak J, Badani H, Cohrs RJ (2015) A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation. J Gen Virol 96:1581–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JY, Mandarino A, Chao MV, Mohr I, Wilson AC (2012) Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons. PLoS Pathog 8:e1002540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi M, Wilson AC, Chao MV, Mohr I (2012) Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor. Genes Dev 26:1527–1532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laguardia JJ, Cohrs RJ, Gilden DH (2000) Numbers of neurons and non-neuronal cells in human trigeminal ganglia. Neurol Res 22:565–566

    Article  CAS  PubMed  Google Scholar 

  • Lewis ME, Warren KG, Jeffrey VM, Shnitka TK (1982) Factors affecting recovery of latent herpes simplex virus from human trigeminal ganglia. Can J Microbiol 28:123–129

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Cohen JI (2013) Varicella-zoster virus ORF12 protein activates the phosphatidylinositol 3-kinase/Akt pathway to regulate cell cycle progression. J Virol 87:1842–1848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahalingam R, Wellish MC, Dueland AN, Cohrs RJ, Gilden DH (1992) Localization of herpes simplex virus and varicella zoster virus DNA in human ganglia. Ann Neurol 31:444–448

    Article  CAS  PubMed  Google Scholar 

  • Mahalingam R, Wellish M, Lederer D, Forghani B, Cohrs R, Gilden D (1993) Quantitation of latent varicella-zoster virus DNA in human trigeminal ganglia by polymerase chain reaction. J Virol 67:2381–2384

    CAS  PubMed  PubMed Central  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Markus A, Lebenthal-Loinger I, Yang IH, Kinchington PR, Goldstein RS (2015) An in vitro model of latency and reactivation of varicella zoster virus in human stem cell-derived neurons. PLoS Pathog 11:e1004885

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagel MA, Rempel A, Huntington J, Kim F, Choe A, Gilden D (2014) Frequency and abundance of alphaherpesvirus DNA in human thoracic sympathetic ganglia. J Virol 88:8189–8192

    Article  PubMed  PubMed Central  Google Scholar 

  • Ouwendijk WJD, Choe A, Nagel A, Gilden D, Osterhaus ADME, Cohrs RJ, Verjans GMGM (2012) Restricted varicella zoster virus transcription in human trigeminal ganglia obtained soon after death. J Virol 86:10203–10206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plotkin SA, Stein S, Snyder M, Immesoete P (1977) Attempts to recover varicella virus from ganglia. Ann Neurol 2:249

    Article  CAS  PubMed  Google Scholar 

  • Plummer G (1973) Isolation of herpesviruses from trigeminal ganglia of man, monkeys, and cats. J Infect Dis 128:345–347

    Article  CAS  PubMed  Google Scholar 

  • Roizman B, Zhou G, Du T (2011) Checkpoints in productive and latent infections with herpes simplex virus 1: conceptualization of the issues. J Neurovirol 17:512–517

    Article  PubMed  Google Scholar 

  • Sadaoka T, Depledge DP, Rajbhandari L, Venkatesan A, Breuer J, Cohen JI (2016) In vitro system using human neurons demonstrates that varicella-zoster vaccine virus is impaired for reactivation, but not latency. Proc Natl Acad Sci U S A 113:E2403–E2412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shahzad A, Gilden D, Cohrs RJ (2015) Translational medicine and varicella zoster virus: need for disease modeling. New Horiz Transl Med 2:89–91

    Article  PubMed  PubMed Central  Google Scholar 

  • Shu M, Du T, Zhou G, Roizman B (2015) Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia. Proc Natl Acad Sci U S A 112:E5420–E5426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steiner I, Kennedy PG, Pachner AR (2007) The neurotropic herpes viruses: herpes simplex and varicella-zoster. Lancet Neurol 6:1015–1028

    Article  CAS  PubMed  Google Scholar 

  • Stevens JG, Haarr L, Porter DD, Cook ML, Wagner EK (1988) Prominence of the herpes simplex virus latency-associated transcript in trigeminal ganglia from seropositive humans. J Infect Dis 158:117–123

    Article  CAS  PubMed  Google Scholar 

  • Theil D, Paripovic I, Derfuss T, Herberger S, Strupp M, Arbusow V, Brandt T (2003) Dually infected (HSV-1/VZV) single neurons in human trigeminal ganglia. Ann Neurol 54:678–682

    Article  PubMed  Google Scholar 

  • Tiwari V, Shukla D (2010) Phosphoinositide 3 kinase signalling may affect multiple steps during herpes simplex virus type-1 entry. J Gen Virol 91:3002–3009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Virgin HW, Wherry EJ, Ahmed R (2009) Redefining chronic viral infection. Cell 138:30–50

    Article  CAS  PubMed  Google Scholar 

  • Vrabec JT (1999) Delayed facial palsy after tympanomastoid surgery. Am J Otol 20:26–30

    CAS  PubMed  Google Scholar 

  • Wang K, Lau TY, Morales M, Mont EK, Straus SE (2005) Laser-capture microdissection: refining estimates of the quantity and distribution of latent herpes simplex virus 1 and varicella-zoster virus DNA in human trigeminal ganglia at the single-cell level. J Virol 79:14079–14087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warren KG, Devlin M, Gilden DH, Wroblewska Z, Brown SM, Subak-Sharpe J, Koprowski H (1977) Isolation of herpes simplex virus from human trigeminal ganglia, including ganglia from one patient with multiple sclerosis. Lancet 2:637–639

    Article  CAS  PubMed  Google Scholar 

  • Warren KG, Brown SM, Wroblewska Z, Gilden DH, Koprowski H, Subak-Sharpe J (1978) Isolation of latent herpes ximplex virus from the superior cervical and vagus ganglions of humans. N Engl J Med 298:1068–1069

    Article  CAS  PubMed  Google Scholar 

  • Wilcox CL, Johnson EM Jr (1988) Characterization of nerve growth factor-dependent herpes simplex virus latency in neurons in vitro. J Virol 62:393–399

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Public Health Service grants NS082228 (R.J.C.), NS093716 (D.G.), and AG032958 (D.G., R.J.C.) from the National Institutes of Health. Hussain Badani was supported by training grant NS007321 to D.G. from the National Institutes of Health. We thank Marina Hoffman for editorial review and Cathy Allen for manuscript preparation.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B-182, Aurora, CO, 80045, USA

    Randall J. Cohrs, Hussain Badani, Nicholas L. Baird, Teresa M. White, Bridget Sanford & Don Gilden

  2. Department of Immunology and Microbiology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B-182, Aurora, CO, 80045, USA

    Randall J. Cohrs & Don Gilden

Authors
  1. Randall J. Cohrs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hussain Badani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas L. Baird
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Teresa M. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bridget Sanford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Don Gilden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Randall J. Cohrs.

Ethics declarations

The left and right human TG were obtained within 24 h of death in accordance with approved protocols from the Colorado Multiple Institutional Review Board and Office for Human Research protections, US Department of Health and Human Services (http://www.hhs.gov/ohrp) and FDA (http://www.fda.gov/oc/ohrt/irbs/default.htm) guidelines.

Conflict of interest

All authors declare that they have no conflict of interest.

Additional information

This work is dedicated to the memory of Don Gilden, M.D.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cohrs, R.J., Badani, H., Baird, N.L. et al. Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia. J. Neurovirol. 23, 152–157 (2017). https://doi.org/10.1007/s13365-016-0480-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-016-0480-1

Keywords

Search

Navigation